Substituted inhibitors of menin-mll and methods of use

ABSTRACT

The present disclosure provides methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The methods are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin. Compositions for use in these methods are also provided.

CROSS-REFERENCE

This application claims the benefit of U.S. Provisional Application No.62/561,089, filed Sep. 20, 2017; U.S. Provisional Application No.62/577,644, filed Oct. 26, 2017; U.S. Provisional Application No.62/595,436, filed Dec. 6, 2017; and U.S. Provisional Application No.62/637,074, filed Mar. 1, 2018, each incorporated herein by reference inits entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Aug. 30, 2018, isnamed 47535729601_SL.txt and is 15,912 bytes in size.

BACKGROUND OF THE INVENTION

The mixed-lineage leukemia (MLL) protein is a histone methyltransferasecritical for the epigenetic regulation of gene transcription. Many acuteleukemias, including acute myeloblastic leukemia (AML), acutelymphoblastic leukemia (ALL) and mixed-lineage leukemia (MLL), arecharacterized by the presence of chimeric MLL fusion proteins thatresult from chromosomal translocations of the MLL gene located atchromosome 11, band q23 (11q23). Chimeric MLL fusion proteins retainapproximately 1,400 amino acids of the N-terminus of MLL, but are fusedwith one of approximately 80 partner proteins (e.g., AF4, AF9, ENL,AF10, ELL, AF6, AF1p, GAS7). MLL fusion proteins lack the originalhistone methyltransferase activity of the C-terminus of MLL and gain theability to regulate transcription of numerous oncogenes, including HOXand MEIS1, resulting in increased cell proliferation and decreased celldifferentiation, ultimately leading to leukemogenesis.

The menin protein, which is encoded by the Multiple Endocrine Neoplasia(MEN) gene, is a ubiquitously expressed nuclear protein that engages ininteractions with DNA processing and repair proteins, chromatinmodifying proteins and numerous transcription factors (Agarwal, et al.;Horm Metab Res, 2005, 37(6): 369-374). The association of menin with theN-terminus of MLL fusion proteins is necessary for the observedoncogenic activity of MLL fusion proteins. This association has beenshown to constitutively up-regulate the expression of HOX and MEIS1oncogenes and impairs proliferation and differentiation of hematopoieticcells leading to leukemia development. Since menin has been shown tofunction as a general oncogenic cofactor in MLL-related leukemias, theinteraction between menin and MLL fusion proteins and MLL represents apotential chemotherapeutic target.

Patients, especially infants, with leukemias harboring chromosomaltranslocations of the MLL gene have a dismal prognosis, with less than a40% five year survival rate (Slany; Haematologica, 2009, 94(7):984-993). A novel therapeutic strategy is urgently needed to treat theseleukemias. Small molecule inhibitors that block the menin-MLLinteraction are thus valuable targets for treating diseases involvingthe MLL fusion proteins.

SUMMARY OF THE INVENTION

The present disclosure addresses a need in the art by providingcompositions and methods for inhibiting the protein-protein interactionof menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositionsand methods herein may be useful for treating diseases dependent on theactivity of MLL1, MLL2, MLL fusion proteins, and/or menin such asleukemia, solid cancers, and diabetes. In some embodiments, a compoundof the disclosure interacts non-covalently with menin and inhibits theinteraction of menin with MLL. In some embodiments, a compound of thedisclosure covalently binds menin and inhibits the interaction of meninwith MLL.

In some embodiments of a compound provided herein, the compoundnon-covalently or covalently binds to any one or more isoforms of menin,for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) orisoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, the meninprotein shares 60% or more, 70% or more, 75% or more, 80% or more, 85%or more, 90% or more, 95% or more, or 99% or more sequence identity withisoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ IDNO: 3).

In one aspect, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

H is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

A is

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L¹, L², and L³ is independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, and—N(R⁵¹)S(O)N(R⁵¹)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹, L², or L³can together optionally form a bridge or ring;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR^(52S)(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

each of R^(H) and R^(B) is, at each occurrence, independently selectedfrom R⁵⁰, or two R^(H) groups or two R^(B) groups attached to the sameatom or different atoms can together optionally form a bridge or ring;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring; and

each of m, p, and q is independently an integer from 0 to 12.

In one aspect, the present disclosure provides a compound of Formula(I-G):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₅₋₆ carbocycle and 5- to 6-membered heterocycle;

H² is selected from C₅₋₆ carbocycle and 5- to 6-membered heterocycle;

A is selected from

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L¹, L², L³ and L⁴ is independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, and—N(R⁵¹)S(O)N(R⁵¹)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹, L², or L³can together optionally form a bridge or ring;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(B) is, at each occurrence, independently selected from R⁵⁰, or twoR^(B) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

R^(H2) is independently selected at each occurrence from R⁵⁰, or twoR^(H2) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring;

r is an integer from 1 to 6; and

each of m, p and q is independently an integer from 0 to 12.

In some embodiments, the compound of Formula (I-G) is represented byFormula (I-I):

In some embodiments, for a compound of Formula (I-G) or (I-I), L⁴ isselected from —O—, —S—, —NH— and —CH₂—, such as L⁴ is selected from —O—and —NH—. In some embodiments, R^(H2) is selected from halo, —C(O)R⁵²,and —C(O)N(R⁵²)₂, optionally wherein R⁵² is selected from hydrogen andC₁₋₁₀ alkyl.

In some embodiments is a compound of Formula (I), wherein C is a C₃₋₁₂carbocycle or 3- to 12-membered heterocycle. In some embodiments is acompound of Formula (I), wherein C is a 5- to 12-membered heterocycle,wherein the heterocycle comprises at least one nitrogen atom. In someembodiments is a compound of Formula (I), wherein C is aromatic. In someembodiments is a compound of Formula (I), wherein C is saturated. Insome embodiments is a compound of Formula (I), wherein C is selectedfrom piperidinyl, piperazinyl, and morpholinyl.

In some embodiments is a compound of Formula (I), wherein C is selectedfrom

In some embodiments is a compound of Formula (I), wherein R⁵⁷ isselected from —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵².In some embodiments is a compound of Formula (I), wherein R⁵⁷ isselected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃. In some embodiments is a compound of Formula (I), whereinR^(C) is selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl. In someembodiments is a compound of Formula (I), wherein R^(C) is selected fromhalogen, —N(R⁵²)₂, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂,C₁₋₃ alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached todifferent atoms can together form a C₁₋₃ bridge.

In some embodiments is a compound of Formula (I), wherein

C is

W¹ is C₁₋₄ alkylene, optionally substituted with one or more R⁵⁰;

W² is selected from a bond; and C₁₋₄ alkylene, optionally substitutedwith one or more R⁵⁰; and

W³ is selected from absent; and C₁₋₄ alkylene, optionally substitutedwith one or more R⁵⁰.

In some embodiments is a compound of Formula (I), wherein C is

W³ and W¹, W², and W³ are each independently selected from C₁₋₄alkylene, wherein each C₁₋₄ alkylene is optionally substituted with oneor more R⁵⁰. In some embodiments is a compound of Formula (I), wherein Cis

and W¹, W², and W³ are each C₁ alkylene. In some embodiments is acompound of Formula (I), wherein C is

and W¹ and W² are each C₁ alkylene and W³ is absent. In some embodimentsis a compound of Formula (I), wherein C is

and R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —C(O)R⁵²,—C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴.

In some embodiments is a compound of Formula (I), wherein L³ comprisesless than 20 atoms. In some embodiments is a compound of Formula (I),wherein L³ is not a bond. In some embodiments is a compound of Formula(I), wherein L³ is C₁₋₆ alkylene optionally substituted with one or moreR⁵⁰. In some embodiments is a compound of Formula (I), wherein L³ is C₂alkylene substituted with at least one C₁₋₃ alkyl or C₁₋₃ haloalkyl, andoptionally further substituted with one or more R⁵⁰. In some embodimentsis a compound of Formula (I), wherein L³ is substituted with ═O, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²)or —O(C₁₋₆ alkyl). In some embodiments is a compound of Formula (I),wherein L³ is substituted with —CH₃. In some embodiments is a compoundof Formula (I), wherein L³ is selected from

In some embodiments is a compound of Formula (I), wherein R⁵⁰ is methyl.In some embodiments is a compound of Formula (I), wherein L³ is selectedfrom

wherein any one of which is optionally substituted with one or more R⁵⁰.In some embodiments is a compound of Formula (I), wherein R⁵⁰ is methyl.In some embodiments is a compound of Formula (I), wherein L³ is selectedfrom

wherein any one of which is optionally substituted with one or more R⁵⁰.

In some embodiments is a compound of Formula (I), wherein H is 5- to12-membered heterocycle and B is 5- to 12-membered heterocycle or C₄₋₈carbocycle. In some embodiments is a compound of Formula (I), wherein Bis 6- to 12-membered bicyclic heterocycle. In some embodiments is acompound of Formula (I), wherein B is 6- to 12-membered bicyclicheterocycle and comprises at least one nitrogen atom. In someembodiments is a compound of Formula (I), wherein B is

wherein each of E and G is independently N or C. In some embodiments isa compound of Formula (I), wherein B is phenylene or

In some embodiments is a compound of Formula (I), wherein R^(B) isselected from halogen, methyl, —CN, —OR⁵², and —N(R⁵²)₂. In someembodiments is a compound of Formula (I), wherein H is 6-membered to12-membered bicyclic heterocycle.

In some embodiments is a compound of Formula (I), wherein H is

X¹ and X² are each independently selected from CR² and N; X³ and X⁴ areeach independently selected from C and N; each of X⁵ and X⁶ isindependently selected from CR⁵³, N, —NR⁴, O, and S; R¹, R² and R³ areeach independently selected at each occurrence from hydrogen and R⁵⁰;and R⁴ is selected from R⁵¹. In some embodiments is a compound ofFormula (I), wherein X³ and X⁴ are each C. In some embodiments is acompound of Formula (I), wherein X⁶ is CR⁵³, and R³ is selected fromhydrogen, halogen, —OR⁵², —N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃haloalkyl. In some embodiments is a compound of Formula (I), wherein H

and R¹, R² and R³ are each independently selected at each occurrencefrom hydrogen and R⁵⁰. In some embodiments is a compound of Formula (I),wherein R² is selected from hydrogen, halogen, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl,C₂₋₃ alkenyl, and C₂₋₃ alkynyl.

In some embodiments is a compound of Formula (I) having the structure:

wherein each of R¹, R² and R³ is independently selected at eachoccurrence from hydrogen and R⁵⁰.

In some embodiments is a compound of Formula (I) having the structure:

wherein each of R¹, R² and R³ is independently selected at eachoccurrence from hydrogen and R⁵⁰. In some embodiments is a compound ofFormula (I) having the structure:

wherein R² is selected from halogen, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃alkenyl, and C₂₋₃ alkynyl.

In some embodiments is a compound of Formula (I), wherein R³ is selectedfrom hydrogen, halogen, —OR⁵², —N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, andC₁₋₃ haloalkyl. In some embodiments is a compound of Formula (I),wherein R¹ is C₁₋₃ haloalkyl. In some embodiments is a compound ofFormula (I), wherein R¹ is

In some embodiments is a compound of Formula (I), wherein H isthienopyrimidinyl or thienopyridinyl. In some embodiments is a compoundof Formula (I), wherein H is

each of X¹ and X² is independently CR² or N; each of X⁷, X⁸, X⁹, and X¹⁰is independently CR¹⁶, CR¹⁷R¹⁸, N, —NR¹⁹, O, or S; each of R¹⁶, R⁷, andR¹⁸ is independently selected at each occurrence from hydrogen and R⁵⁰;and R¹⁹ is selected from R⁵¹. In some embodiments is a compound ofFormula (I), wherein X¹ is CR², and R² is selected from hydrogen,halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵²,C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. Insome embodiments is a compound of Formula (I), wherein X² is N. In someembodiments is a compound of Formula (I), wherein H is

each of Y¹, Y², and Y⁴ is independently CR², N, —NR²¹, O, or S; Y⁵ isCR²⁰, N, —NR²¹, O, or S; Y⁶ is C or N; Y³ is a bond, CR²², or N, whereinwhen Y³ is CR²² or N, then each of Y¹, Y², and Y⁴ is independently CR²,N, or NR²¹ and Y⁵ is CR²⁰, N, or NR²¹; each of R² and R²⁰ isindependently selected at each occurrence from hydrogen and R⁵⁰; and R²1is selected from R⁵¹.

In some embodiments is a compound of Formula (I), wherein A is

In some embodiments is a compound of Formula (I), wherein A is

In some embodiments is a compound of Formula (I), wherein Z⁵ and Z⁶ areN. In some embodiments is a compound of Formula (I), wherein R^(A2) is,at each occurrence, independently selected from hydrogen, halo, C₁₋₄alkyl, C₁₋₄ alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, —CN, —NO₂, and —OH.

In some embodiments is a compound of Formula (I), wherein L¹ is a bondor —N(R⁵¹)—. In some embodiments is a compound of Formula (I), whereinL¹ is not a bond. In some embodiments is a compound of Formula (I),wherein L is —NH—. In some embodiments is a compound of Formula (I),wherein L² is not a bond. In some embodiments is a compound of Formula(I), wherein L² is alkylene or heteroalkylene, each of which isoptionally substituted with one or more R⁵⁰. In some embodiments is acompound of Formula (I), wherein L² is C₁₋₄ alkylene, optionallysubstituted with one or more R⁵⁰. In some embodiments is a compound ofFormula (I), wherein L² is substituted with ═O. In some embodiments is acompound of Formula (I), wherein L² is —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. In some embodiments is a compound ofFormula (I), wherein L² is —CH₂—.

In some embodiments is a compound of Formula (I), wherein H is 5- to12-membered heterocycle; B is indolylene; and C is 5- to 6-memberedheterocycle. In some embodiments is a compound of Formula (I), wherein His thienopyrimidinyl or thienopyridinyl; B is indolylene; and C ispiperidinyl, piperazinyl, or morpholinyl. In some embodiments is acompound of Formula (I), wherein H is thienopyrimidinyl orthienopyridinyl; B is indolylene; and L¹, L², and L³ are not bonds. Insome embodiments is a compound of Formula (I), wherein H isthienopyrimidinyl or thienopyridinyl; B is indolylene; and C ispiperidinyl, piperazinyl, or morpholinyl. In some embodiments is acompound of Formula (I), wherein H is thienopyrimidinyl orthienopyridinyl; B is 6- to 12-membered bicyclic heterocycle; m is aninteger from 0 to 3; and p is an integer from 0 to 3. In someembodiments is a compound of Formula (I), wherein H isthienopyrimidinyl; B is indolylene; L¹ and L² are each independentlyselected from —O—, —S—, —NH—, and —CH₂—; L³ is selected from bond, —O—,—S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—,—C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of L³ can together optionally form a ring;R^(B) and R^(C) are each independently selected at each occurrence fromR⁵⁰ or two R^(B) groups or two R^(C) groups attached to the same atom ordifferent atoms can together optionally form a ring; m is an integerfrom 0 to 3; p is an integer from 0 to 6; and q is an integer from 0 to6. In some embodiments is a compound of Formula (I), wherein H isthienopyrimidinyl; B is indolylene; L¹ and L² are each independentlyselected from —O—, —S—, —NH—, and —CH₂—; L³ is selected from C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of which isoptionally substituted with one or more R⁵⁰; R^(B) and R^(C) are eachindependently selected at each occurrence from R⁵⁰, or two R^(B) groupsor two R^(C) groups attached to the same atom or different atoms cantogether optionally form a bridge or ring; m is an integer from 0 to 3;p is an integer from 0 to 3; and q is an integer from 0 to 6.

In some embodiments is a compound of Formula (I), wherein H is

and R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl,C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In some embodiments is a compound ofFormula (I), wherein R² is selected from —NH₂, —CH₃, and —NHCH₃.

In some embodiments is a compound of Formula (I), wherein A is selectedfrom:

In one aspect, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

H is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

A is selected from

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L¹, L², and L³ is independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R)—, and—N(R⁵¹)S(O)N(R)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹, L², or L³can together optionally form a bridge or ring;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

each of R^(H) and R^(B) is, at each occurrence, independently selectedfrom R⁵⁰, or two R^(H) groups or two R^(B) groups attached to the sameatom or different atoms can together optionally form a bridge or ring;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring; and

each of m, p, and q is independently an integer from 0 to 12.

In some embodiments is a compound of Formula (I), wherein the compoundis provided as a substantially pure stereoisomer. In some embodiments isa compound of Formula (I), wherein the stereoisomer is provided in atleast 90% enantiomeric excess.

In certain aspects, the present disclosure provides a pharmaceuticalcomposition comprising a compound or salt of Formula (I) and apharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition is formulated for oral administration. Insome embodiments, the pharmaceutical composition is formulated forinjection.

In certain aspects, the present disclosure provides a method of treatingcancer in a subject, comprising administering to the subject in needthereof an effective amount of a compound or salt of Formula (I). Insome embodiments, the present disclosure provides a method of treating ahematological cancer, comprising administering to a subject in needthereof an effective amount of a compound or salt of Formula (I). Insome embodiments, the present disclosure provides a method of treating ahematological cancer in a subject exhibiting a mutation in thenucleophosmin (NPM1) gene, DNA (cytosine-5)-methyltransferase 3A(DNMT3A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitratedehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (IDH2) gene, orcombination thereof, comprising administering to the subject atherapeutically effective amount of a compound or salt of Formula (I).In some embodiments, the present disclosure provides a method oftreating a hematological cancer in a subject in need thereof,comprising: (a) determining the presence or absence of one or more of anNPM1 mutation, DNMT3A mutation, FLT3 mutation, IDH1 mutation, or IDH2mutation in a biological sample isolated from the subject; and (b) ifthe one or more of the NPM1 mutation, DNMT3A mutation, FLT3 mutation,IDH1 mutation, or IDH2 mutation is determined to be present in thesubject, administering to the subject a therapeutically effective amountof a compound or salt of Formula (I). In some embodiments, the presentdisclosure provides a method of treating a hematological cancer in asubject, comprising administering to the subject in need thereof aneffective amount of a compound or salt of Formula (I) wherein thehematological cancer is leukemia. In some embodiments, the presentdisclosure provides a method of treating a hematological cancer in asubject, comprising administering to the subject in need thereof aneffective amount of a compound or salt of Formula (I) wherein thehematological cancer is lymphoma. In some embodiments, the presentdisclosure provides a method of treating a hematological cancer in asubject, comprising administering to the subject in need thereof aneffective amount of a compound or salt of Formula (I) wherein thehematological cancer is mixed lineage leukemia (MLL), MLL-relatedleukemia, MLL-associated leukemia, MLL-positive leukemia, MLL-inducedleukemia, rearranged mixed lineage leukemia (MLL-r), leukemia associatedwith a MLL rearrangement or a rearrangement of the MLL gene, acuteleukemia, chronic leukemia, indolent leukemia, lymphoblastic leukemia,lymphocytic leukemia, myeloid leukemia, myelogenous leukemia, childhoodleukemia, acute lymphocytic leukemia (ALL), acute myeloid leukemia(AML), acute granulocytic leukemia, acute nonlymphocytic leukemia,chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML),myeloproliferative disease (MPD), myeloproliferative neoplasia (MPN),plasma cell neoplasm, multiple myeloma, myelodysplasia, cutaneous T-celllymphoma, lymphoid neoplasm, AIDS-related lymphoma, thymoma, thymiccarcinoma, mycosis fungoides, Alibert-Bazin syndrome, granulomafungoides, Sezary Syndrome, hairy cell leukemia, T-cell prolymphocyticleukemia (T-PLL), large granular lymphocytic leukemia, meningealleukemia, leukemic leptomeningitis, leukemic meningitis, multiplemyeloma, Hodgkin's lymphoma, non Hodgkin's lymphoma, or Waldenstrom'smacroglobulinemia. In some embodiments, the present disclosure providesa method of treating a hematological cancer in a subject, comprisingadministering to the subject in need thereof an effective amount of acompound or salt of Formula (I) wherein the hematological cancer isselected from a malignant lymphoma, a leukemia, a mature B cellneoplasm, a mature T cell and natural killer (NK) cell neoplasm, aprecursor lymphoid neoplasm, Hodgkin lymphoma (HL), a plasma cell tumor,a mast cell tumor, a neoplasm of histiocytes and accessory lymphoidcells, an immunoproliferative disease, a myeloid leukemia, and amyelodysplastic syndrome (MDS). In some embodiments, the presentdisclosure provides a method of treating a hematological cancer in asubject, comprising administering to the subject in need thereof aneffective amount of a compound or salt of Formula (I) wherein thehematological cancer is selected from acute myeloid leukemia, acutelymphocytic leukemia, chronic myeloid leukemia, non-Hodgkin's lymphoma,multiple myeloma, mixed lineage leukemia and myelodysplastic syndromes.In some embodiments, the present disclosure provides a method oftreating a hematological cancer in a subject, comprising administeringto the subject in need thereof an effective amount of a compound or saltof Formula (I) wherein the hematological cancer is selected from acutemyeloid leukemia.

In another aspect, the present disclosure provides a method of treatinga subject having acute myeloid leukemia or acute lymphoblastic leukemia,comprising: (a) screening the subject for the presence of an MLLrearrangement, a partial tandem duplication of MLL, or elevated MEIS1expression levels; and (b) administering a compound or salt of Formula(I) to the subject if one or more of the MLL rearrangement, partialtandem duplication of MLL, or elevated MEIS1 expression levels aredetermined to be present.

In certain aspects, the present disclosure provides a method of treatinginsulin resistance, pre-diabetes, diabetes, or risk of diabetes in asubject, comprising administering to the subject in need thereof aneffective amount of a compound or salt of Formula (I). In certainaspects, the present disclosure provides a method of treatinghyperglycemia in a subject, comprising administering to the subject inneed thereof an effective amount of a compound or salt of Formula (I).

In certain aspects, the present disclosure provides a method of treatinga disease or condition associated with MLL fusion proteins, comprisingadministering to a subject in need thereof an effective amount of acompound or salt of Formula (I).

In certain aspects, the present disclosure provides a method of treatinga disorder mediated by chromosomal rearrangement on chromosome 11q23 ina subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound or salt ofFormula (I). In certain aspects, the present disclosure provides amethod of treating a disorder mediated by an interaction between meninand another protein, comprising administering to a subject in needthereof a therapeutically effective amount of a compound or salt ofFormula (I). In some embodiments, the subject is a human.

In certain aspects, the present disclosure provides a method ofpromoting proliferation of a pancreatic cell, comprising administering acompound or salt of Formula (I). In some embodiments, the presentdisclosure provides a method of promoting proliferation of a pancreaticcell, comprising administering a compound or salt of Formula (I),wherein the pancreatic cell is an islet cell. In some embodiments, thepresent disclosure provides a method of promoting proliferation of apancreatic cell, comprising administering a compound or salt of Formula(I), wherein the pancreatic cell is a beta cell. In some embodiments,the present disclosure provides a method of promoting proliferation of apancreatic cell, comprising administering a compound or salt of Formula(I), wherein the pancreatic cell is a beta cell and beta cellproliferation is evidenced by an increase in beta cell production. Insome embodiments, the present disclosure provides a method of promotingproliferation of a pancreatic cell, comprising administering a compoundor salt of Formula (I), wherein the pancreatic cell is a beta cell andbeta cell proliferation is evidenced by an increase in insulinproduction. In some embodiments, the present disclosure provides amethod of promoting proliferation of a pancreatic cell, comprisingadministering a compound or salt of Formula (I) to a subject. In someembodiments, the present disclosure provides a method of promotingproliferation of a pancreatic cell, comprising administering a compoundor salt of Formula (I) to a subject, wherein the subject is human.

In certain aspects, the present disclosure provides a method ofinhibiting an interaction of menin with one or more of MLL1, MLL2, anMLL fusion protein, and an MLL Partial Tandem Duplication, comprisingcontacting menin with an effective amount of a compound or salt ofFormula (I). In certain aspects, the present disclosure provides amethod of inhibiting a menin-MLL interaction, comprising contactingmenin with an effective amount of a compound or salt of Formula (I),wherein inhibition of the interaction is evidenced by a reduction inexpression of an MLL fusion protein target gene. In certain aspects, thepresent disclosure provides a method of inhibiting a menin-MLLinteraction, comprising contacting menin with an effective amount of acompound or salt of Formula (I), wherein inhibition of the interactionis evidenced by a reduction in expression of an MLL fusion proteintarget gene and the MLL fusion protein target gene is HOXA9, DLX2, PBX3,or MEIS1. In certain aspects, the present disclosure provides a methodof stabilizing menin, comprising contacting menin with a compound orsalt of Formula (I).

The contacting may comprise contacting a cell that expresses menin. Insome embodiments, the method comprises administering a secondtherapeutic agent. In some embodiments, the contacting takes place invivo. In some embodiments, the contacting takes place in vitro.

In certain aspects, the present disclosure provides a kit comprising apharmaceutical composition described herein and instructions for usingthe composition to treat a subject suffering from a disease or conditionmediated by an interaction between menin and another protein.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims.

A better understanding of the features and advantages of the presentinvention will be obtained by reference to the following detaileddescription that sets forth illustrative embodiments, in which theprinciples of the invention are utilized, and the accompanying drawingsof which:

FIG. 1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO:1).

FIG. 2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO:2).

FIG. 3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO:3).

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

“MLL fusion protein” refers to a protein with an N-terminal fragment ofMLL fused with a partner protein. Non-limiting examples of a partnerprotein include 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22,9p13.3, 9p22 (MLLT3/AF9), AB11, AB12, ACACA, ACTN4, AFF1/AF4, AFF3/LAF4,AFF4/AF5, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13,C2CD3, CASC5, CASP8AP2, CBL, CEP164, CEP170B, CREBBP, DCP1A, DCPS,EEFSEC/SELB, ELL, EPS15, FLNA, FNBP1, FOXO3, GAS7, GMPS, KIAA1524,LAMC3, LOC100131626, MAML2, ME2, MLLT1/ENL, MLLT10/AF10, MLLT11/AF1Q,MLLT3/AF9, MLLT4/AF6, MLLT6/AF17, MYH11, MYO1F, NA, NEBL, —NRIP3, PDS5A,PICALM, PRPF19, PTD, RUNDC3B, SEPT11, SEPT2, SEPT5, SEPT6, SEPT9, SMAP1,TET1, TNRC18, TOP3A, VAV1, and Xq26.3 (CT45A2). MLL fusion proteins maybe created through the joining of a gene that codes for an MLL proteinand a gene that codes for a partner protein creating a fusion gene.Translation of this fusion gene may result in a single or multiplepolypeptides with functional properties derived from each of theoriginal proteins.

The term “C_(x-y)” or “C_(x)-C_(y)” when used in conjunction with achemical moiety, such as alkyl, alkenyl, or alkynyl is meant to includegroups that contain from x to y carbons in the chain. For example, theterm “C_(x-y) alkyl” refers to substituted or unsubstituted saturatedhydrocarbon groups, including straight-chain alkyl and branched-chainalkyl groups that contain from x to y carbons in the chain. The terms“C_(x-y) alkenyl” and “C_(x-y) alkynyl” refer to substituted orunsubstituted straight-chain or branched-chain unsaturated hydrocarbongroups that contain at least one double or triple bond respectively.Unless stated otherwise specifically in the specification, a C_(x-y)alkyl, C_(x-y) alkenyl, or C_(x-y) alkynyl is optionally substituted byone or more substituents such as those substituents described herein.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring inwhich each atom of the ring is a carbon atom. Carbocycle may include 3-to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle maybe selected from saturated, unsaturated, and aromatic rings. In someembodiments, the carbocycle is an aryl. In some embodiments, thecarbocycle is a cycloalkyl. In some embodiments, the carbocycle is acycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g.,phenyl, may be fused to a saturated or unsaturated ring, e.g.,cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated,unsaturated and aromatic bicyclic rings, as valence permits, areincluded in the definition of carbocyclic. Exemplary carbocycles includecyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, andnaphthyl. Unless stated otherwise specifically in the specification, acarbocycle is optionally substituted by one or more substituents such asthose substituents described herein.

“Heterocycle” refers to a saturated, unsaturated or aromatic ringcomprising one or more heteroatoms. Exemplary heteroatoms include N, O,Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclicrings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridgedrings. Each ring of a bicyclic heterocycle may be selected fromsaturated, unsaturated, and aromatic rings. The heterocycle may beattached to the rest of the molecule through any atom of theheterocycle, valence permitting, such as a carbon or nitrogen atom ofthe heterocycle. In some embodiments, the heterocycle is a heteroaryl.In some embodiments, the heterocycle is a heterocycloalkyl. In anexemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to asaturated or unsaturated ring, e.g., cyclohexane, cyclopentane, orcyclohexene.

“Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprisesat least one heteroatom wherein each heteroatom may be independentlyselected from N, O, and S. As used herein, the heteroaryl ring may beselected from monocyclic or bicyclic and fused or bridged ring systemsrings wherein at least one of the rings in the ring system is aromatic,i.e., it contains a cyclic, delocalized (4n+2) in-electron system inaccordance with the Hückel theory. The heteroatom(s) in the heteroarylmay be optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the heteroaryl, valence permitting,such as a carbon or nitrogen atom of the heteroaryl. Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryls as defined above whichare optionally substituted by one or more substituents such as thosesubstituents described herein.

Compounds of the present disclosure also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof.

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scopeof the present disclosure. For example, hydrogen has three naturallyoccurring isotopes, denoted ¹H (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may afford certain therapeutic advantages, suchas increased in vivo half-life and/or exposure, or may provide acompound useful for investigating in vivo routes of drug elimination andmetabolism. Isotopically-enriched compounds may be prepared byconventional techniques well known to those skilled in the art.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetricatoms but are not mirror images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R—Ssystem. When a compound is a pure enantiomer, the stereochemistry ateach chiral carbon can be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) in which theyrotate plane polarized light at the wavelength of the sodium D line.Certain compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms, the asymmetric centers of which can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible stereoisomers, including racemic mixtures, opticallypure forms, mixtures of diastereomers and intermediate mixtures.Optically active (R)- and (S)-isomers can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.The optical activity of a compound can be analyzed via any suitablemethod, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over theother isomer can be determined.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E-form (or cis- or trans-form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, chemical entities described hereinare intended to include all Z-, E- and tautomeric forms as well.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the structure. Itwill be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.Substituents can include any substituents described herein, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, aheterocycloalkyl, an aromatic and heteroaromatic moiety. In someembodiments, substituents may include any substituents described herein,for example: halogen, hydroxy, oxo (═O), thioxo (═S), cyano (—CN), nitro(—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂), —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(C)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,and heteroarylalkyl any of which may be optionally substituted by alkyl,alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl,oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(C)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);wherein each R^(a) is independently selected from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein eachR^(a), valence permitting, may be optionally substituted with alkyl,alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo(═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(C)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);and wherein each R^(b) is independently selected from a direct bond or astraight or branched alkylene, alkenylene, or alkynylene chain, and eachR^(C) is a straight or branched alkylene, alkenylene or alkynylenechain.

It will be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to a“heteroaryl” group or moiety implicitly includes both substituted andunsubstituted variants.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “salt” or “pharmaceutically acceptable salt” refers to saltsderived from a variety of organic and inorganic counter ions well knownin the art. Pharmaceutically acceptable acid addition salts can beformed with inorganic acids and organic acids. Inorganic acids fromwhich salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toaffect the intended application, including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofplatelet adhesion and/or cell migration. The specific dose will varydepending on the particular compounds chosen, the dosing regimen to befollowed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

As used herein, “treatment” or “treating” refers to an approach forobtaining beneficial or desired results with respect to a disease,disorder, or medical condition including but not limited to atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. In certain embodiments, forprophylactic benefit, the compositions are administered to a subject atrisk of developing a particular disease, or to a subject reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof.

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction (e.g., activity, expression, binding, protein-proteininteraction) of a target protein (e.g., menin, MLL1, MLL2, and/or an MLLfusion protein). Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein.While preferred antagonists herein specifically interact with (e.g.,bind to) the target, compounds that inhibit a biological activity of thetarget protein by interacting with other members of the signaltransduction pathway of which the target protein is a member are alsospecifically included within this definition. A preferred biologicalactivity inhibited by an antagonist is associated with the development,growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g., bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human. “Mammal” includeshumans and both domestic animals such as laboratory animals andhousehold pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses,rabbits), and non-domestic animals such as wildlife and the like.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., compound of Formula (I)). Thus, theterm “prodrug” refers to a precursor of a biologically active compoundthat is pharmaceutically acceptable. In some aspects, a prodrug isinactive when administered to a subject but is converted in vivo to anactive compound, for example, by hydrolysis. The prodrug compound oftenoffers advantages of solubility, tissue compatibility or delayed releasein a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs(1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., et al.,“Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. Symposium Series,Vol. 14; and Bioreversible Carriers in Drug Design, ed. Edward B. Roche,American Pharmaceutical Association and Pergamon Press) each of which isincorporated in full by reference herein. The term “prodrug” is alsomeant to include any covalently bonded carriers, which release theactive compound in vivo when such prodrug is administered to a mammaliansubject. Prodrugs of an active compound, as described herein, aretypically prepared by modifying functional groups present in the activecompound in such a way that the modifications are cleaved, either inroutine manipulation or in vivo, to the parent active compound. Prodrugsinclude compounds wherein a hydroxy, amino or mercapto group is bondedto any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject. In vitro assays encompass cell-based assays inwhich cells alive or dead are employed. In vitro assays also encompass acell-free assay in which no intact cells are employed.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye, colorant, flavor enhancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

The present disclosure provides compounds for modulating the interactionof menin with proteins such as MLL1, MLL2 and MLL-fusion oncoproteins.In certain embodiments, the disclosure provides compounds and methodsfor inhibiting the interaction of menin with its upstream or downstreamsignaling molecules including but not limited to MLL1, MLL2 andMLL-fusion oncoproteins. Compounds of the disclosure may be used inmethods for the treatment of a wide variety of cancers and otherdiseases associated with one or more of MLL1, MLL2, MLL fusion proteins,and menin. In certain embodiments, a compound of the disclosurecovalently binds menin and inhibits the interaction of menin with MLL.In certain embodiments, a compound of the disclosure interactsnon-covalently with menin and inhibits the interaction of menin withMLL.

Compounds of the disclosure may be used in methods for treating a widevariety of diseases associated with MLL1, MLL2, MLL fusion proteins, andmenin. In certain embodiments, a compound of the disclosure interactsnon-covalently with menin and inhibits the interaction of menin withMLL. In certain embodiments, a compound of the disclosure covalentlybinds menin and inhibits the interaction of menin with MLL.

In some aspects, the present disclosure provides a compound or salt thatselectively binds to the menin protein and/or modulates the interactionof menin with an MLL protein (e.g., MLL1, MLL2, or an MLL fusionprotein). In certain embodiments, the compound modulates the meninprotein by binding to or interacting with one or more amino acids and/orone or more metal ions. Certain compounds may occupy the F9 and/or P13pocket of menin. The binding of a compound disclosed herein may disruptmenin or MLL (e.g., MLL1, MLL2, or an MLL fusion protein) downstreamsignaling.

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

A is

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L¹, L², and L³ is independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, and—N(R⁵¹)S(O)N(R⁵¹)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹, L², or L³can together optionally form a bridge or ring;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

each of R^(H) and R^(B) is, at each occurrence, independently selectedfrom R⁵⁰, or two R^(H) groups or two R^(B) groups attached to the sameatom or different atoms can together optionally form a bridge or ring;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring; and

each of m, p, and q is independently an integer from 0 to 12.

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

A is selected from

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L^(t), L², L³ and L⁴ is independently selected from bond, —O—,—S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—,—C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, and—N(R⁵¹)S(O)N(R⁵¹)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹, L², or L³can together optionally form a bridge or ring;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and —N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(B) is, at each occurrence, independently selected from R⁵⁰, or twoR^(B) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

R^(H) is, at each occurrence, independently selected from R⁵⁰ and-L⁴-H²—(R^(H2))_(r);

H² is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

R^(H2) is independently selected at each occurrence from R⁵⁰, or twoR^(H2) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

r is an integer from 1 to 6;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring; and

each of m, p, and q is independently an integer from 0 to 12.

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

A is

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L¹ and L² is independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, and—N(R⁵¹)S(O)N(R⁵¹)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹ or L² cantogether optionally form a bridge or ring;

L³ is C₁₋₆ alkylene, optionally substituted with one or more R⁵⁰;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

each of R^(H) and R^(B) is, at each occurrence, independently selectedfrom R⁵⁰, or two R^(H) groups or two R^(B) groups attached to the sameatom or different atoms can together optionally form a bridge or ring;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring; and

each of m, p, and q is independently an integer from 0 to 12.

In some embodiments, for a compound of Formula (I), H is 5- to12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle,optionally substituted with one or more R⁵⁰. In some embodiments, Hcontains one or more heteroatoms, such as 1, 2, 3, 4, 5 or 6 ringheteroatoms. In some embodiments, H contains at least 1, 2, 3, 4 or 5ring nitrogen atoms. In some embodiments, H is thienopyrimidinyl,optionally substituted with one or more R⁵⁰. In some embodiments, H issubstituted with C₁₋₄ haloalkyl, such as —CH₂CF₃. In some embodiments, His substituted with one or more R⁵⁰ (e.g., by replacing a hydrogenconnected to a ring atom with a bond to R⁵⁰). H may be substituted with0, 1, 2, 3, 4, 5, 6 or more R⁵⁰ groups. H may be substituted with 1, 2,3, 4, 5 or 6 R⁵⁰ groups, such as H substituted with 1 or 2 R⁵⁰ groups.In some embodiments, H is substituted with at least 1, 2, 3, 4, 5 or 6R⁵⁰ groups. In some embodiments, H is substituted with up to 6, 5, 4, 3,2 or 1 R⁵⁰ groups.

In some embodiments, for a compound of Formula (I), H is

wherein X¹ and X² are each independently selected from CR² and N; X³ andX⁴ are each independently selected from C and N; X⁵ and X⁶ are eachindependently selected from CR⁵³, N, —NR⁴, O, and S; R¹, R² and R³ areeach independently selected at each occurrence from hydrogen and R⁵⁰;and R⁴ is selected from R⁵¹. In some embodiments, X³ and X⁴ are each C.In some embodiments, X¹ is CR², and R² is selected from hydrogen,halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵²,—CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl,and C₂₋₃ alkynyl, such as R² is selected from —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, and C₁₋₂ alkyl. In some embodiments, R² is methyl or—NHCH₃. In some embodiments, R² is H. In some embodiments, X² is N. Insome embodiments, X⁶ is CR⁵³, and R³ is selected from hydrogen, halogen,—OH, —N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In someembodiments, X⁵ is S. In some embodiments, at least one of X⁵ and X⁶ isselected from N, —NR⁴, O and S. In some embodiments, R¹ is C₁₋₃haloalkyl, such as —CH₂CF₃. In some embodiments, X¹ is CR², X² is N, X³and X⁴ are each C, X⁵ is S, X⁶ is CR⁵³, and R¹ is selected from R⁵⁰. Insome embodiments, X¹ is CR²; X² is N; X³ and X⁴ are each C; X⁵ is S; X⁶is CH; R¹ is C₁₋₃ haloalkyl; and R² is selected from hydrogen, halogen,—OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂,—CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃alkynyl. In some embodiments, H is

In some embodiments, H is

such as

In some embodiments, H is

and R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In someembodiments, R² is selected from hydrogen, halogen, —OH, alkoxy (e.g.,—OR⁵², —OCH₃, —OCH₂CH₃), aminoalkyl, alkylamino, —N(R⁵²)₂ (e.g., —NH₂,—NHCH₃, —NHCH₂CH₃), —N(CH₃)₂, —CN, C₁₋₃ alkyl (e.g., —CH₃), cyclopropyl,C₁₋₃ alkyl-OR⁵² (e.g., —CH₂OH, —CH₂OC(O)CH₃), C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl.

In some embodiments, for a compound of Formula (I), H is

wherein R¹ is selected from H, halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl,heteroalkyl, and haloalkyl; R² is selected from hydrogen, halogen,—OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl; and R³ ishydrogen or alkyl. In some embodiments, for a compound of Formula (I), His

wherein R¹ is cyano; R² is selected from —OR⁵², —NH₂, —N(R⁵²)₂, —CN, andC₁₋₃ alkyl; and R³ is hydrogen.

In some embodiments, for a compound of Formula (I), L¹ is a bond. Insome embodiments, for a compound of Formula (I), L¹ is not a bond. Insome embodiments, for a compound of Formula (I), L¹ comprises less than20 atoms, such as less than 10 atoms. In some embodiments, L¹ comprisesless than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In someembodiments, L¹ comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 orat least 20 atoms. In some embodiments, L¹ comprises at least oneheteroatom, such as L¹ comprises at least one nitrogen. In someembodiments, L is substituted with one or more R⁵⁰. In some embodiments,L¹ is unsubstituted. In some embodiments, L¹ is selected from bond, —O—,—S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—,—N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂, —S(O)—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene,heteroalkylene, and heteroalkenylene. In some embodiments, L¹ isselected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—,—OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—,—S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, C₁₋₆ alkyleneand C₂₋₆ alkenylene, wherein the C₁₋₆ alkylene and C₂₋₆ alkenylene areeach optionally substituted with one or more R⁵⁰. In some embodiments,L¹ is —N(R⁵¹)—, such as —NH—. In some embodiments, L¹ is selected from—O—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, C₁₋₄ alkylene, C₂₋₄ alkenylene, and C₁₋₄heteroalkylene. In some embodiments, L¹ is —N(R⁵¹)—, wherein R⁵¹ isselected from hydrogen and alkyl.

In some embodiments, for a compound of Formula (I), A is selected from

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), and each of Z¹, Z²,Z³ and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), and each of Z¹, Z², Z³, and Z⁴ is independentlyselected from —C(R^(A1))(R^(A2))—. In some embodiments, for a compoundof Formula (I), and Z¹ is —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))— and eachof Z², Z³, and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—,and —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), and each of Z¹ and Z² is—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))— and each of Z³ and Z⁴ isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), and Z³ is —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—and each of Z¹, Z², and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, and —C(R^(A1))(R^(A2))—C(R^(A))(R^(A2))—. In someembodiments, for a compound of Formula (I), and each of Z³ and Z⁴ is—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))— and each of Z¹ and Z² isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z¹ is —C(O)— and each of Z², Z³, and Z⁴ isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z³ is —C(O)— and each of Z¹, Z², and Z⁴ isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z¹ is —C(R^(A1))(R^(A2))—C(O)— and each of Z²,Z³, and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z³ is —C(R^(A1))(R^(A2))—C(O)— and each of Z¹,Z², and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), R^(A1) is, at each occurrence, hydrogen. Insome embodiments, for a compound of Formula (I), R^(A2) is, at eachoccurrence, hydrogen. In some embodiments, for a compound of Formula(I), A is selected from

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), A is

In some embodiments, for a compound of Formula (I), and each of Z¹, Z²,Z³, and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), and each of Z¹, Z², Z³, and Z⁴ is independentlyselected from —C(R^(A1))(R^(A2))—. In some embodiments, for a compoundof Formula (I), and Z¹ is —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))— and eachof Z², Z³, and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—,and —C(R^(A1))(R^(A2))—C(R^(A))(R^(A2))—. In some embodiments, for acompound of Formula (I), and each of Z¹ and Z² is—C(R^(A1))(R^(A1))—C(R^(A1))(R^(A1))— and each of Z³ and Z⁴ isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), and Z³ is —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—and each of Z¹, Z², and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, and —C(R^(A1))(R^(A2))—C(R^(A))(R^(A2))—. In someembodiments, for a compound of Formula (I), and each of Z³ and Z⁴ is—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))— and each of Z¹ and Z² isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z¹ is —C(O)— and each of Z², Z³, and Z⁴ isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z³ is —C(O)— and each of Z¹, Z², and Z⁴ isindependently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z¹ is —C(R^(A1))(R^(A2))—C(O)— and each of Z²,Z³, and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), Z³ is —C(R^(A1))(R^(A2))—C(O)— and each of Z¹,Z², and Z⁴ is independently selected from —C(R^(A1))(R^(A2))—, and—C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—. In some embodiments, for acompound of Formula (I), R^(A1) is, at each occurrence, hydrogen. Insome embodiments, for a compound of Formula (I), R^(A2) is, at eachoccurrence, hydrogen. In some embodiments, for a compound of Formula(I), A is selected from

In some embodiments, for a compound of Formula (I), Z² is absent. Insome embodiments, Z³ is absent. In some embodiments, Z² and Z³ areabsent.

In some embodiments, for a compound of Formula (I), L² is a bond. Insome embodiments, for a compound of Formula (I), L² is not a bond. Insome embodiments, for a compound of Formula (I), L² comprises less than20 atoms, such as less than 10 atoms. In some embodiments, L² comprisesless than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. In someembodiments, L² comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15 orat least 20 atoms. In some embodiments, L² comprises at least oneheteroatom, such as L² comprises at least one nitrogen. In someembodiments, L² is C₁₋₁₀ alkylene, such as C₁₋₄ alkylene, optionallysubstituted with one or more R⁵⁰. In some embodiments, L² is substitutedwith one or more R⁵⁰. In some embodiments, L² is unsubstituted. In someembodiments, L² is selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene, heteroalkylene, andheteroalkenylene. In some embodiments, L² is selected from bond, —O—,—S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—,—N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, C₁₋₆ alkylene and C₂₋₆ alkenylene,wherein the C₁₋₆ alkylene and C₂₋₆ alkenylene are each optionallysubstituted with one or more R⁵⁰. In some embodiments, L² is selectedfrom —O—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, C₁₋₄ alkylene and C₁₋₄ heteroalkylene. Insome embodiments, L² is selected from —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. In some embodiments, L² is —CH₂—.

In some embodiments, for a compound of Formula (I), B is 3- to12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle.In some embodiments, the heterocycle comprises at least one nitrogenatom. In some embodiments, B is 6- to 12-membered heterocycle, whereinthe heterocycle comprises at least 1, 2, 3 or 4 ring heteroatomsselected from N, O and S. In some embodiments, B is a 6,5- or6,6-bicyclic heterocycle. In some embodiments, B comprises at least onering nitrogen. In some embodiments, B is indolylene, such as

optionally substituted with one or more R^(B). In some embodiments, B is

In some embodiments, B is selected from

wherein M¹, M², M³ and M⁴ are each independently selected from CR⁷, Nand NR⁹; M⁵ is selected from C and N; M⁶, M⁷ and M⁸ are eachindependently selected from CR⁸, N, —NR⁹, O and S; M⁹, M¹⁰ and M¹¹ areeach independently selected from CR¹⁰, CR¹¹R¹², —NR¹³, O and S; R⁷, R⁸,R¹⁰, R¹¹, and R¹² are each independently selected from hydrogen and R⁵⁰;and R⁹ and R¹³ are each independently selected from R⁵¹, wherein B maybe connected at any ring atom to L² or L³ (e.g., by replacing a hydrogenconnected to a ring atom with a bond to L² or L³).

In some embodiments, B is selected from

In some embodiments, B is

In some embodiments, B is phenylene or

In some embodiments, B is substituted with one or more R^(B) (e.g., byreplacing a hydrogen connected to a ring atom with a bond to R^(B)). Bmay be substituted with 0, 1, 2, 3, 4, 5, 6 or more R^(B) groups. B maybe substituted with 1, 2, 3, 4, 5 or 6 R^(B) groups, such as Bsubstituted with 1 or 2 R^(B) groups. In some embodiments, B issubstituted with at least 1, 2, 3, 4, 5 or 6 R^(B) groups. In someembodiments, B is substituted with p R^(B) groups, wherein p is aninteger from 0 to 6. In some embodiments, p is 0, 1, 2, 3, 4, 5 or 6. Insome embodiments, p is at least 1, 2, 3, 4, 5 or 6. In some embodiments,p is up to 6, 5, 4, 3, 2, or 1. In some embodiments, p is an integerfrom 1 to 3.

In some embodiments, R^(B) is independently selected at each occurrencefrom halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl,aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl,cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino,cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl,aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino. In some embodiments, R^(B) is independentlyselected at each occurrence from halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl,heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino,heterocyclylalkyl, and heteroarylalkyl. In some embodiments, two R^(B)groups attached to the same atom or different atoms can together form aring.

In some embodiments, for a compound of Formula (I), L³ is a bond. Insome embodiments, for a compound of Formula (I), L³ is not a bond. Insome embodiments, for a compound of Formula (I), L³ comprises less than30 atoms, such as less than 20 atoms. In some embodiments, L³ comprisesless than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms. Insome embodiments, L³ comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,15 or at least 20 atoms. In some embodiments, L³ comprises at least oneheteroatom, such as L³ comprises at least one nitrogen. In someembodiments, L³ is C₁₋₁₀ alkylene, such as C₁₋₄ alkylene, optionallysubstituted with one or more R⁵⁰. In some embodiments, L³ is substitutedwith one or more R⁵⁰. In some embodiments, L³ is unsubstituted. In someembodiments, L³ is selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene, heteroalkylene, andheteroalkenylene. In some embodiments, L³ is C₁₋₆ alkylene, optionallysubstituted with one or more R⁵⁰, wherein R⁵⁰ is selected fromdeuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵². In some embodiments,L³ is —CH₂CH(R⁵⁰)—, such as —CH₂CH(CH₃)—. In some embodiments, two R⁵⁰groups attached to the same atom or different atoms of L³ optionallyform a bridge or ring, such as a cyclopropyl ring. In some embodiments,L³ is substituted with R⁵⁰, wherein R⁵⁰ forms a bond to ring C. In someembodiments, L³ is substituted with one or more groups selected fromdeuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵². In some embodiments,L³ is substituted with —CH₃. In some embodiments, L³ is C₂ alkylenesubstituted with at least one C₁₋₃ alkyl or C₁₋₃ haloalkyl, andoptionally further substituted with one or more R⁵⁰. In someembodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl).

In some embodiments, for a compound of Formula (I), L³ is selected from

and

Optionally, R⁵⁰ is methyl. L³ may be selected from

In some embodiments, L³ is

In some embodiments, L³ is

In some embodiments, L³ comprises a stereocenter. In some embodiments,the stereocenter is in the R-configuration. In some embodiments, thestereocenter is in the S-configuration. In some embodiments, theR-isomer of L³ is provided in at least 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9% excess over the S-isomer. In some embodiments,the S-isomer of L³ is provided in at least 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9% excess over the R-isomer.

In some embodiments, for a compound of Formula (I), C is azetidinylene,piperidinylene or piperazinylene; R⁵⁷ is —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, or—NR⁵²S(═O)₂R⁵²; and L³ is substituted with one or more R⁵⁰, wherein L³is not —CH₂CH(OH)—. In some embodiments, C is azetidinylene,piperidinylene or piperazinylene; R⁵⁷ is —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, or—NR⁵²S(═O)₂R⁵²; and L³ is substituted with C₁₋₄ alkyl or C₁₋₄ haloalkyl.

In some embodiments, for a compound of Formula (I), L³ is selected from

and any combination thereof. In some embodiments, for a compound ofFormula (I), L³ is selected from

In some embodiments, for a compound of Formula (I), C is 3- to12-membered heterocycle, such as 5- to 12-membered heterocycle. In someembodiments, the heterocycle is saturated. In some embodiments, C isselected from 5- to 7-membered monocyclic heterocycle, 8- to 10-memberedfused bicyclic heterocycle, and 7- to 12-membered spirocyclicheterocycle. In some embodiments, the heterocycle comprises at least onenitrogen atom, such as one or two nitrogen atoms. In some embodiments, Ccomprises at least one ring nitrogen. In some embodiments, C is selectedfrom piperidinyl and piperazinyl, such as

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

optionally substituted with one or more R^(C), wherein R⁵⁷ is selectedfrom hydrogen and R⁵⁰. In some embodiments, C is selected from

wherein R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such asR⁵⁷ is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃,and —S(═O)₂NHCH₃.

In some embodiments, for a compound of Formula (I), C is selected from

In some embodiments, for a compound of Formula (I), R⁵⁷ is selected from—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),—C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, each of which isindependently substituted at each occurrence with one or moresubstituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)NH(C₁₋₆alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂N⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃.

In some embodiments, for a compound of Formula (I), C is substitutedwith one or more R^(C) (e.g., by replacing a hydrogen connected to aring atom with a bond to R^(C)). C may be substituted with 0, 1, 2, 3,4, 5, 6 or more R^(C) groups. C may be substituted with 1, 2, 3, 4, 5 or6 R^(C) groups, such as C substituted with 1 or 2 R^(C) groups. In someembodiments, C is substituted with at least 1, 2, 3, 4, 5 or 6 R^(C)groups. In some embodiments, C is unsubstituted. In some embodiments, Cis substituted with q R^(C) groups, wherein q is an integer from 0 to 6.In some embodiments, q is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, qis at least 1, 2, 3, 4, 5 or 6. In some embodiments, q is up to 6, 5, 4,3, 2, or 1. In some embodiments, p is 0. In some embodiments, q is 1 or2. In some embodiments, for a compound of Formula (I), C isazetidinylene, piperidinylene or piperazinylene; R⁵⁷ is —S(═O)₂R⁵⁸,—S(═O)₂N(R⁵²)₂, or —NR⁵²S(═O)₂R⁵²; and p is an integer from 1 to 6.

In some embodiments, for a compound of Formula (I), R^(C) is selectedfrom —C(O)R⁵², —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², ═O, C₁₋₃ alkyl, and C₁₋₃ haloalkyl, or two R^(C) groupsattached to different atoms can together form a C₁₋₃ bridge. In someembodiments, R^(C) is selected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, suchas —CH₃.

In some embodiments, C is selected from

In some embodiments, for a compound of Formula (I), C is substitutedwith R^(C), wherein R^(C) comprises a functional group that reacts withone or more residues on menin to form a covalent bond. In someembodiments, R^(C) reacts with one or more cysteine residues on menin,such as cysteine 329 or cysteine 334, to form a covalent bond. In someembodiments, R^(C) comprises an α, β-unsaturated carbonyl, an α,β-unsaturated sulfonyl, an epoxide, an aldehyde, a sulfonyl fluoride, ahalomethylcarbonyl, a dihalomethylcarbonyl, a trihalomethylcarbonyl oran alkene. In some embodiments, R^(C) is —NR⁵²C(O)R⁵², wherein R⁵² isindependently selected from hydrogen and alkene. In some embodiments,R^(C) is —NHC(O)CHCH₂.

In some embodiments, for a compound of Formula (I), H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais

and B is 3- to 12-membered heterocycle. In some embodiments, for acompound of Formula (I), H is 5- to 12-membered heterocycle, optionallysubstituted with one or more R⁵⁰; A is

and B is 3- to 12-membered heterocycle. In some embodiments, H is 6- to12-membered bicyclic heterocycle, optionally substituted with one ormore R⁵⁰; A is

and B is 3- to 12-membered heterocycle. In some embodiments, H is 6- to12-membered bicyclic heterocycle, optionally substituted with one ormore R⁵⁰; A is

and B is 3- to 12-membered heterocycle. In some embodiments, H is 6- to12-membered bicyclic heterocycle, optionally substituted with one ormore R⁵⁰; A is

and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His 6- to 12-membered bicyclic heterocycle, optionally substituted withone or more R⁵⁰; A is

and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰; A is

and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰; A is

and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His thienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is

and B is 3- to 12-membered heterocycle. In some embodiments H isthienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is

and B is 3-to 12-membered heterocycle. In some embodiments, H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais selected from

and B is 3- to 12-membered heterocycle. In some embodiments, H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais selected from

and B is 3- to 12-membered heterocycle. In some embodiments, H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais

and B is indolylene. In some embodiments, H is 5- to 12-memberedheterocycle, optionally substituted with one or more R⁵⁰; A is

and B is indolylene. In some embodiments, H is thienopyrimidinylsubstituted with one or more R⁵⁰; A is selected from

and B is indolylene. In some embodiments, H is thienopyrimidinylsubstituted with one or more R⁵⁰; A is selected from

and B is indolylene.

In some embodiments, for a compound of Formula (I), H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais

B is 3- to 12-membered heterocycle; C is 3- to 12-membered heterocycle;m is an integer from 0 to 3; and p is an integer from 1 to 3. In someembodiments, for a compound of Formula (I), H is 5- to 12-memberedheterocycle, optionally substituted with one or more R⁵⁰; A is

B is 3- to 12-membered heterocycle; C is 3- to 12-membered heterocycle;m is an integer from 0 to 3; and p is an integer from 1 to 3. In someembodiments, H is 6- to 12-membered bicyclic heterocycle, optionallysubstituted with one or more R⁵⁰; A is

B is 6- to 12-membered bicyclic heterocycle; C is 3- to 12-memberedheterocycle; m is an integer from 0 to 3; and p is an integer from 1 to3. In some embodiments, H is 6- to 12-membered bicyclic heterocycle,optionally substituted with one or more R⁵⁰; A is

B is 6- to 12-membered bicyclic heterocycle; C is 3- to 12-memberedheterocycle; m is an integer from 0 to 3; and p is an integer from 1 to3. In some embodiments, H is 5- to 12-membered heterocycle, optionallysubstituted with one or more R⁵⁰; A is 3- to 12-membered heterocycle; Bis 3- to 12-membered heterocycle; and C is 3- to 12-memberedheterocycle. In some embodiments, H is 6- to 12-membered bicyclicheterocycle, optionally substituted with one or more R⁵⁰; A is

B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-memberedheterocycle. In some embodiments, H is 6- to 12-membered heterocycle,optionally substituted with one or more R⁵⁰; A is

B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-memberedheterocycle. In some embodiments, H is 6- to 12-membered bicyclicheterocycle, optionally substituted with one or more R⁵⁰; A is selectedfrom

B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-memberedheterocycle. In some embodiments, H is 6- to 12-membered bicyclicheterocyle, optionally substituted with one or more R⁵⁰; A is selectedfrom

B is 6- to 12-membered bicyclic heterocycle; and C is 3- to 12-memberedheterocycle. In some embodiments, H is 6- to 12-membered bicyclicheterocycle, optionally substituted with one or more R⁵⁰; A is selectedfrom

B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to3; and p is an integer from 1 to 3. In some embodiments, H is 6- to12-membered bicyclic heterocycle, optionally substituted with one ormore R⁵⁰; A is selected from

B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to3; and p is an integer from 1 to 3. In some embodiments, H isthienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is

and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His thienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is

and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His thienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is

B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to3; and p is an integer from 1 to 3. In some embodiments, H isthienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is

B is 6- to 12-membered bicyclic heterocycle; m is an integer from 0 to3; and p is an integer from 1 to 3. In some embodiments, H is 9- to10-membered bicyclic heterocycle, optionally substituted with one ormore R⁵⁰; A is

and B is 9-membered bicyclic heterocycle, wherein each of saidheterocycles comprises at least one nitrogen atom. In some embodiments,H is 9- to 10-membered bicyclic heterocycle, optionally substituted withone or more R⁵⁰; A is

and B is 9-membered bicyclic heterocycle, wherein each of saidheterocycles comprises at least one nitrogen atom. In some embodiments,H is 9- to 10-membered bicyclic heterocycle, optionally substituted withone or more R⁵⁰; A is

B is 9-membered bicyclic heterocycle; and p is an integer from 1 to 3,wherein each of said heterocycles comprises at least one nitrogen atom.In some embodiments, H is 9- to 10-membered bicyclic heterocycle,optionally substituted with one or more R⁵⁰; A is

B is 9-membered bicyclic heterocycle; and p is an integer from 1 to 3,wherein each of said heterocycles comprises at least one nitrogen atom.

In some embodiments, for a compound of Formula (I), L¹ comprises lessthan 10 atoms, L² comprises less than 10 atoms, and L³ comprises lessthan 20 atoms. In some embodiments, L¹ is a bond and L² and L³ eachcomprise at least 1 atom. In some embodiments, L¹ is a bond and L² andL³ each comprise at least 1 atom. In some embodiments, L² is a bond andL¹ and L³ each comprise at least 1 atom. In some embodiments, L³ is abond and L¹ and L² each comprise at least 1 atom. In some embodiments,L¹, L² and L³ each comprise at least 1 atom, such as at least 2 atoms.In some embodiments, L¹, L² and L³ are each independently selected frombond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R)S(O)₂N(R⁵¹)—, alkylene, alkenylene,heteroalkylene, and heteroalkenylene. In some embodiments, L¹, L² and L³are each independently selected from —CH₂—, —CH₂CH₂—, —CH₂CH(CH₃)—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. In someembodiments, L¹ is selected from —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene, heteroalkylene, andheteroalkenylene; and L² and L³ are independently selected from C₁₋₄alkylene, optionally substituted with one or more R⁵⁰. In someembodiments, L¹, L² and L³ are each independently selected from —O—,—S—, —N(R⁵¹)—; C₁₋₄ alkylene and 1- to 4-membered heteroalkylene, eachof which is optionally substituted with one or more R⁵⁰. In someembodiments, L¹ is —NH—, L² is —CH₂—, and L³ is C₁₋₄ alkylene,optionally substituted with one or more R⁵⁰.

In certain aspects, for a compound of Formula (I):

H is 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰;

A is

B and C are each independently selected from 3- to 12-memberedheterocycle;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a ring;

R^(B) and R^(C) are each independently selected at each occurrence fromR⁵⁰, or two R^(B) groups or two R^(C) groups attached to the same atomor different atoms can together optionally form a ring;

m is an integer from 0 to 3;

p is an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In certain aspects, for a compound of Formula (I):

H is thienopyrimidinyl, optionally substituted with one or more R⁵⁰;

A is selected from

B is indolylene;

L¹ and L² are each independently selected from —O—, —S—, —NH—, and—CH₂—; L³ is selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene,alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, eachof which is optionally substituted with one or more R⁵⁰, wherein two R⁵⁰groups attached to the same atom or different atoms of L³ can togetheroptionally form a ring;

R^(B) and R^(C) are each independently selected at each occurrence fromR⁵⁰, or two R^(B) groups or two R^(C) groups attached to the same atomor different atoms can together optionally form a ring;

m is an integer from 0 to 3;

p is an integer from 0 to 6;

R⁵⁷ is selected from:

-   -   —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, R¹ is selected from R⁵⁰. In some embodiments, R¹ isC₁₋₃ haloalkyl, such as —CH₂CF₃. In some embodiments, R² is selectedfrom R⁵⁰. In some embodiments, R² is selected from hydrogen, halogen,—OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In someembodiments, R² is selected from halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such asR² is selected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl.Optionally, R² is selected from —NH₂, —CH₃, —OCH₃, —CH₂OH, and —NHCH₃.In some embodiments, R³ is selected from hydrogen, halogen, —OH,—N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In someembodiments, L² is selected from —O—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R¹)S(O)₂—, —S(O)₂N(R⁵¹⁾—, C₁₋₄ alkyleneand C₁₋₄ heteroalkylene. In some embodiments, L² is C₁₋₄ alkylene,optionally substituted with one or more R⁵⁰. In some embodiments, L² isC₁₋₂ alkylene, optionally substituted with one or more R⁵⁰. In someembodiments, L² is selected from —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. In some embodiments, L² is —CH₂—. Insome embodiments, R^(B) is present at one or more positions of theindole, such as at position 2, 3, 4, or 6 of the indole. In someembodiments, R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —NR⁵²C(O)R⁵², —C(O)N(R⁵²)₂,—C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, optionallysubstituted C₁₋₁₀ alkyl, optionally substituted C₂₋₁₀ alkenyl, andoptionally substituted C₂₋₁₀ alkynyl. In some embodiments, R^(B) isselected from halogen, —CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, C₁₋₃ alkyl, andoptionally substituted C₁₋₃ alkyl, such as R^(B) is selected fromhalogen, —CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, and C₁₋₂ alkyl. In someembodiments, p is an integer from 1 to 4, such as an integer from 2 to3. In some embodiments, p is 2. In some embodiments, L³ is selected fromC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of which issubstituted with one or more R⁵⁰. In some embodiments, L³ is C₁₋₆alkylene, optionally substituted with one or more R⁵⁰. In someembodiments, L³ is C₂ alkylene substituted with at least one C₁₋₃ alkylor C₁₋₃ haloalkyl, and optionally further substituted with one or moreR⁵⁰. In some embodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆alkyl). In some embodiments, L³ is substituted with —CH₃. In someembodiments, L³ is selected from

where R⁵⁰ is optionally methyl. In some embodiments, C is 3- to12-membered heterocycle, such as 5- to 12-membered heterocycle. In someembodiments, the heterocycle is saturated. In some embodiments, C isselected from 5- to 7-membered monocyclic heterocycle, 8- to 10-memberedfused bicyclic heterocycle, and 7- to 12-membered spirocyclicheterocycle. In some embodiments, the heterocycle comprises at least onenitrogen atom, such as one or two nitrogen atoms. In some embodiments, Ccomprises at least one ring nitrogen. In some embodiments, C is selectedfrom piperidinyl and piperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected from

wherein R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such asR⁵⁷ is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃,and —S(═O)₂NHCH₃. In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴. Insome embodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, p is selected from an integer 0 to 4, such as p is selectedfrom an integer 0 to 2. In some embodiments, p is 0. In someembodiments, R⁵⁷ is selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴, and C₁₋₆ alkyl and C₂₋₆ alkenyl, eachof which is independently substituted at each occurrence with one ormore substituents selected from —S(═O)₂R⁵, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵, —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃.

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, R² is selected from R⁵⁰. In some embodiments, R² isselected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃alkenyl, and C₂₋₃ alkynyl. In some embodiments, R² is selected fromhalogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵²,—CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl,and C₂₋₃ alkynyl, such as R² is selected from —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Optionally, R² is selected from —NH₂,—CH₃, —OCH₃, —CH₂OH, and —NHCH₃. In some embodiments, R^(B) is selectedfrom halogen, —CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,—OC(O)R⁵², —NR⁵²C(O)R⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀alkynyl. In some embodiments, R^(B) is selected from halogen, —CN,—OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, C₁₋₃ alkyl, and optionally substituted C₁₋₃alkyl, such as R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, and C₁₋₂ alkyl. In some embodiments, L³ is selected from C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of which issubstituted with one or more R⁵⁰. In some embodiments, L³ is C₁₋₆alkylene, optionally substituted with one or more R⁵⁰. In someembodiments, L³ is C₂ alkylene substituted with at least one C₁₋₃ alkylor C₁₋₃ haloalkyl, and optionally further substituted with one or moreR⁵⁰. In some embodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆alkyl). In some embodiments, L³ is substituted with —CH₃. In someembodiments, L³ is selected from

where R⁵⁰ is optionally methyl. In some embodiments, C is 3- to12-membered heterocycle, such as 5- to 12-membered heterocycle. In someembodiments, the heterocycle is saturated. In some embodiments, C isselected from 5- to 7-membered monocyclic heterocycle, 8- to 10-memberedfused bicyclic heterocycle, and 7- to 12-membered spirocyclicheterocycle. In some embodiments, the heterocycle comprises at least onenitrogen atom, such as one or two nitrogen atoms. In some embodiments, Ccomprises at least one ring nitrogen. In some embodiments, C is selectedfrom piperidinyl and piperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected

wherein R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(═O)R⁵², —S(—O0)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such asR⁵⁷ is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃,and —S(═O)₂NHCH₃. In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴. Insome embodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, q is selected from an integer 0 to 4, such as q is selectedfrom an integer 0 to 2. In some embodiments, q is 0. In someembodiments, R⁵⁷ is selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, eachof which is independently substituted at each occurrence with one ormore substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃.

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, C is selected from 5- to 7-membered monocyclicheterocycle, such as piperidinyl and piperazinyl. In some embodiments,R⁵⁰ is selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵²,such as R⁵⁰ is methyl. In some embodiments, R⁵⁷ is selected from—S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such as R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃. In some embodiments, R⁵⁷ is —S(═O)₂CH₃. In someembodiments, R⁵⁰ is methyl and R⁵⁷ is —S(═O)₂CH₃. In some embodiments,R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN,C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂,C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such as R² is selectedfrom —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl. In someembodiments, R² is methyl or —NHCH₃. In some embodiments, R² is H. Insome embodiments, C is 3- to 12-membered heterocycle, such as 5- to12-membered heterocycle. In some embodiments, the heterocycle issaturated. In some embodiments, C is selected from 5- to 7-memberedmonocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle,and 7- to 12-membered spirocyclic heterocycle. In some embodiments, theheterocycle comprises at least one nitrogen atom, such as one or twonitrogen atoms. In some embodiments, C comprises at least one ringnitrogen. In some embodiments, C is selected from piperidinyl andpiperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected from

wherein R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such asR⁵⁷ is selected from —S(—O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃,and —S(═O)₂NHCH₃. In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵. In someembodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, q is selected from an integer 0 to 4, such as q is selectedfrom an integer 0 to 2. In some embodiments, q is 0. In someembodiments, R⁵⁷ is selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, eachof which is independently substituted at each occurrence with one ormore substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃.

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, C is selected from 5- to 7-membered monocyclicheterocycle, such as piperidinyl and piperazinyl. In some embodiments,R⁵⁰ is selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵²,such as R⁵⁰ is methyl. In some embodiments, R⁵⁷ is selected from—S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such as R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃. In some embodiments, R⁵⁷ is —S(═O)₂CH₃. In someembodiments, R⁵⁰ is methyl and R⁵⁷ is —S(═O)₂CH₃. In some embodiments,R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN,C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂,C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such as R² is selectedfrom —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl. In someembodiments, R² is methyl or —NHCH₃. In some embodiments, R² is H. Insome embodiments, C is 3- to 12-membered heterocycle, such as 5- to12-membered heterocycle. In some embodiments, the heterocycle issaturated. In some embodiments, C is selected from 5- to 7-memberedmonocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle,and 7- to 12-membered spirocyclic heterocycle. In some embodiments, theheterocycle comprises at least one nitrogen atom, such as one or twonitrogen atoms. In some embodiments, C comprises at least one ringnitrogen. In some embodiments, C is selected from piperidinyl andpiperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected from

wherein R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such asR⁵⁷ is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃. In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴. Insome embodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, q is selected from an integer 0 to 4, such as q is selectedfrom an integer 0 to 2. In some embodiments, q is 0. In someembodiments, R⁵⁷ is selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, eachof which is independently substituted at each occurrence with one ormore substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(═O)R⁵²,—S(═O)₂R⁵, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃.

In certain aspects, for a compound of Formula (I):

H is 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰;

A is

B is a C₃₋₁₂ carbocycle;

C is a bond;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹), —N(R⁵¹)C(N⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—,—S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R)S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)N(R⁵¹)—;alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, andheteroalkynylene, each of which is optionally substituted with one ormore R⁵⁰, wherein two R⁵⁰ groups attached to the same atom or differentatoms of any one of L¹, L² or L³ can together optionally form a ring;

R^(B) is independently selected at each occurrence from R⁵⁰, or twoR^(B) groups attached to the same atom or different atoms can togetheroptionally form a ring;

p is an integer from 0 to 6;

q is 0;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In certain aspects, for a compound of Formula (I):

H is

each of R¹, R² and R³ is independently selected at each occurrence fromhydrogen and R⁵⁰;

A is

B is a C₃₋₆ carbocycle;

C is a bond;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a ring;

each R^(B) is selected at each occurrence from R⁵⁰, or two R^(B) groupsattached to the same atom or different atoms can together optionallyform a ring;

p is an integer from 0 to 6;

q is 0;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, R² is selected from R⁵⁰. In some embodiments, R² isselected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃alkenyl, and C₂₋₃ alkynyl. In some embodiments, R² is selected fromhalogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵²,—CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl,and C₂₋₃ alkynyl, such as R² is selected from —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Optionally, R² is selected from —NH₂,—CH₃, —OCH₃, —CH₂OH, and —NHCH₃. In some embodiments, R⁵⁷ is selectedfrom —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),—C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, each of which isindependently substituted at each occurrence with one or moresubstituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)NH(C₁₋₆alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(═O)₂NHCH₃.

In certain aspects, for a compound of Formula (I):

H is

each of R¹, R² and R³ is independently selected at each occurrence fromhydrogen and R⁵⁰;

A is

B is a 3- to 12-membered heterocycle;

C is a bond;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a ring;

each R^(B) is selected at each occurrence from R⁵⁰, two R^(B) groupsattached to the same atom or different atoms can together optionallyform a ring;

p is an integer from 0 to 6;

q is 0;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵²—NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   —S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In certain aspects, a compound of Formula (I) may be represented by:

wherein R² is selected from R⁵⁰ and R^(B) is selected from halogen, —CN,—OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, C₁₋₃ alkyl, and optionally substituted C₁₋₃alkyl.

In some embodiments, R² is selected from halogen, —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In some embodiments, R² isselected from halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl,—CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such as R² is selected from—OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl. In some embodiments, R²is selected from —NH₂, —CH₃, —OCH₃, —CH₂OH, and —NHCH₃. In someembodiments, R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂, andC₁₋₂ alkyl.

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, H is selected from C₃₋₁₂ carbocycle and 3- to12-membered heterocycle, and H² is selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle. In some embodiments, H is selected from C₅₋₆carbocycle and 5- to 6-membered heterocycle, and H² is selected fromC₅₋₆ carbocycle and 5- to 6-membered heterocycle. In some embodiments, His selected from C₆ carbocycle and 6-membered heterocycle, such asphenyl, pyridyl, or pyrimidinyl. In some embodiments, L⁴ is selectedform —O—, —S—, —NH— and —CH₂—. In some embodiments, H² is selected fromC₆ carbocycle and 6-membered heterocycle, such as phenyl. In someembodiments, H² is substituted with at least one fluoro. In someembodiments, R^(H2) is selected from R⁵⁰. In some embodiments, R^(H2) isselected from halo, —C(O)R⁵², and —C(O)N(R⁵²)₂. In some embodiments,R^(H2) is selected from halo, —C(O)R⁵², and —C(O)N(R⁵²)₂, wherein R⁵² isselected from hydrogen and C₁₋₁₀ alkyl. In some embodiments, H² is

optionally further substituted with one or more R^(H2). In someembodiments, H² is

In certain aspects, a compound of Formula (I) may be represented by:

In some embodiments, L⁴ is selected from —O— and —NH—

In certain aspects, the present disclosure provides a compound ofFormula (I-G):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₅₋₆ carbocycle and 5- to 6-membered heterocycle;

H² is selected from C₅₋₆ carbocycle and 5- to 6-membered heterocycle;

A is selected from

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—;

Z⁵ and Z⁶ is independently selected from —C(H)— and —N—;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is selected from bond, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle;

each of L¹, L², L³ and L⁴ is independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, and—N(R⁵¹)S(O)N(R⁵¹)— or from alkylene, alkenylene, alkynylene,heteroalkylene, heteroalkenylene, and heteroalkynylene, each of which isoptionally substituted with one or more R⁵⁰, wherein two R⁵⁰ groupsattached to the same atom or different atoms of any one of L¹, L², or L³can together optionally form a bridge or ring;

R⁵⁰ is, at each occurrence, independently selected from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle, wherein each        C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle in R⁵⁰ is        independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle;

R^(A1) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(A2) is, at each occurrence, independently selected from hydrogen andR⁵⁰;

R^(B) is, at each occurrence, independently selected from R⁵⁰, or twoR^(B) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

R^(H2) is independently selected at each occurrence from R⁵⁰, or twoR^(H2) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

R^(C) is, at each occurrence, independently selected from hydrogen orR⁵⁰, or two R^(C) groups attached to the same atom or different atomscan together optionally form a bridge or ring;

r is an integer from 1 to 6; and

each of m, p and q is independently an integer from 0 to 12.

In certain embodiments, the present disclosure provides a stereoisomerof a compound of Formula (I). In some embodiments, the stereoisomer isin enantiomeric excess. In some embodiments, the stereoisomer isprovided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or99.9%, enantiomeric excess. In some embodiments, the stereoisomer isprovided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer isin greater than 95% enantiomeric excess, such as greater than 99%enantiomeric excess.

In certain embodiments, the present disclosure provides a stereoisomerof a compound of Formula (I). In some embodiments, the stereoisomer isin diastereomeric excess. In some embodiments, the stereoisomer isprovided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or99.9%, diastereomeric excess. In some embodiments, the stereoisomer isprovided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,or 99.9%, diastereomeric excess. In some embodiments, the stereoisomeris in greater than 95% diastereomeric excess, such as greater than 99%diastereomeric excess.

In certain embodiments, the compound of Formula (I) is preferably usedas a non-racemic mixture, wherein one enantiomer is present in excess ofits corresponding enantiomer. Typically, such mixture will contain amixture of the two isomers in a ratio of at least about 9:1, preferablyat least 19:1. In some embodiments, the compound is provided in at least96% enantiomeric excess, meaning the compound has less than 2% of thecorresponding enantiomer. In some embodiments, the compound is providedin at least 96% diastereomeric excess, meaning the compound has lessthan 2% of the corresponding diastereomer.

In certain embodiments, the compound of Formula (I) is preferably usedas a non-racemic mixture wherein the (+)-isomer is the major componentof the mixture. Typically, such mixture will contain no more than about10% of the (−)-isomer, meaning the ratio of (+)- to (−)-isomers is atleast about 9:1, and preferably less than 5% of the (−)-isomer, meaningthe ratio of (+)- to (−)-isomers is at least about 19:1. In someembodiments, the compound used has less than 2% of the (−)-isomer,meaning it has an enantiomeric excess of at least about 96%. In someembodiments, the compound has an enantiomeric excess of at least 98%. Insome embodiments, the compound has an enantiomeric excess of at least99%.

In certain embodiments, the compound of Formula (I) is preferably usedas a non-racemic mixture wherein the (−)-isomer is the major componentof the mixture. Typically, such mixture will contain no more than about10% of the (+)-isomer, meaning the ratio of (−)- to (+)-isomers is atleast about 9:1, and preferably less than 5% of the (+)-isomer, meaningthe ratio of (−)- to (+)-isomers is at least about 19:1. In someembodiments, the compound used has less than 2% of the (+)-isomer,meaning it has an enantiomeric excess of at least about 96%. In someembodiments, the compound has an enantiomeric excess of at least 98%. Insome embodiments, the compound has an enantiomeric excess of at least99%.

In certain aspects, a compound of the disclosure covalently binds tomenin and inhibits the interaction of menin with MLL. Such bonding maylead to an increase in the affinity of the compound for menin, which isan advantageous property in many applications, including therapeutic anddiagnostic uses. In some embodiments, the compounds of the disclosurecomprise electrophilic groups capable of reacting with a nucleophilicgroup present in a menin protein. Suitable electrophilic groups aredescribed throughout the application, while suitable nucleophilic groupsinclude, for example, cysteine moieties present in the binding domain ofa menin protein. Without wishing to be bound by theory, a cysteineresidue in the menin binding domain may react with the electrophilicgroup of a compound of the disclosure, leading to formation of aconjugate product. In some embodiments, the compounds of the disclosureare capable of covalently bonding to the cysteine residue at position329 of a menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform1 (SEQ ID NO: 1). In some embodiments, the disclosure provides aconjugate of a compound of the disclosure with a menin protein. Forexample, the disclosure provides a conjugate of a compound of thedisclosure with menin, bound at the cysteine residue 329 of meninisoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO:1).

In some embodiments, for a compound of Formula (I), one or more of R^(B)and R^(C), when present, comprises a functional group that covalentlyreacts with one or more residues on menin. In some embodiments, thefunctional group covalently reacts with one or more cysteine residues onmenin. In some embodiments, the functional group covalently reacts witha cysteine on menin at position 329 relative to SEQ ID NO: 2 whenoptimally aligned or position 334 relative to SEQ ID NO: 1 whenoptimally aligned. In some embodiments, the functional group covalentlyreacts with one or more residues on menin selected from cysteine 329,cysteine 241, and/or cysteine 230 on menin relative to SEQ ID NO: 2 whenoptimally aligned. In some embodiments, the functional group covalentlyreacts with cysteine 329 relative to SEQ ID NO: 2 when optimallyaligned.

In some embodiments, for a compound of Formula (I), one or more of R^(B)and R^(C), when present, comprises a moiety that covalently reacts withone or more residues on menin. In some embodiments, one or more of R^(B)and R^(C), when present, comprises a moiety that covalently reacts withone or more isoforms of menin, for example, isoform 1 (SEQ ID NO: 1),isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3) of menin. Incertain embodiments, one or more of R^(B) and R^(C), when present,comprises a moiety that covalently reacts with menin, wherein the meninprotein shares 60% or more, 70% or more, 75% or more, 80% or more, 85%or more, 90% or more, 95% or more, or 99% or more sequence identity withisoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ IDNO: 3).

In some embodiments, for a compound of Formula (I), one or more of R^(B)and R^(C), when present, comprises an electrophilic group that issusceptible to nuclephilic attack from a residue on menin. Any suitableelectrophilic moiety known to one of skill in the art to bind tonuclephilic residues, for example, any electrophilic moiety known tobind to cysteine residues, is contemplated herein. In some embodiments,one or more of R^(B) and R^(C), when present, comprises a moiety otherthan an electrophile, wherein the moiety is capable of binding to orcovalently reacting with a residue on menin. In some embodiments, acompound or salt of Formula (I) is capable of (a) binding covalently tomenin and (b) inhibiting the interation of menin and MLL.

In some embodiments, for a compound of Formula (I), R^(C) comprises afunctional group that covalently reacts with one or more residues onmenin. In some embodiments, the functional group covalently reacts withone or more cysteine residues on menin. In some embodiments, thefunctional group covalently reacts with a cysteine on menin at position329 relative to SEQ ID NO: 2 when optimally aligned or position 334relative to SEQ ID NO: 1 when optimally aligned.

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen to provide stable moieties andcompounds.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques known in theart. Materials used herein are either commercially available or preparedby synthetic methods generally known in the art. These schemes are notlimited to the compounds listed in the examples or by any particularsubstituents, which are employed for illustrative purposes. Althoughvarious steps are described and depicted in Scheme 1 and Examples 1-11,the steps in some cases may be performed in a different order than theorder shown in Scheme 1 and Examples 1-11. Various modifications tothese synthetic reaction schemes may be made and will be suggested toone skilled in the art having referred to the disclosure contained inthis Application. Numberings or R groups in each scheme do notnecessarily correspond to that of the claims or other schemes or tablesherein.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period of about 1 to about 24 hours;reactions left to run overnight average a period of about 16 hours.

In general, compounds of the disclosure may be prepared by the followingreaction scheme:

In some embodiments, a compound of Formula A-7 may be prepared accordingto Scheme 1. For example, methanesulfonyl chloride can be added to asolution of alcohol A-1 and triethylamine to afford mesylate A-2.Addition of mesylate A-2 to a solution of Cs₂CO₃ and amine A-3 canprovide a compound of Formula A-4. Coupling of A-4 to amine A-5 canproceed according to methods known in the art to give a compound ofFormula A-6. Addition of TFA can reveal the free amine, which canoptionally be reacted with R⁵⁷-LG, wherein LG is a suitable leavinggroup, to afford a compound of Formula A-7.

In some embodiments, a compound of the present disclosure, for example,a compound of a formula given in Table 1, is synthesized according toone of the general routes outlined in Scheme 1, Examples 1-11, or bymethods generally known in the art. In some embodiments, exemplarycompounds may include, but are not limited to, a compound or saltthereof selected from Table 1.

TABLE 1 No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

Pharmaceutical Compositions

The compositions and methods of the present disclosure may be utilizedto treat an individual in need thereof. In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound or salt of Formula (I) and apharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is formulated fororal administration. In other embodiments, the pharmaceuticalcomposition is formulated for injection. In still more embodiments, thepharmaceutical compositions comprise a compound as disclosed herein andan additional therapeutic agent (e.g., anticancer agent). Non-limitingexamples of such therapeutic agents are described herein below.

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a composition of a compound or salt of Formula(I) is administered in a local rather than systemic manner, for example,via injection of the compound directly into an organ, often in a depotpreparation or sustained release formulation. In specific embodiments,long acting formulations are administered by implantation (for examplesubcutaneously or intramuscularly) or by intramuscular injection.Furthermore, in other embodiments, a compound or salt of Formula (I) isdelivered in a targeted drug delivery system, for example, in a liposomecoated with organ-specific antibody. In such embodiments, the liposomesare targeted to and taken up selectively by the organ. In yet otherembodiments, the composition is provided in the form of a rapid releaseformulation, in the form of an extended release formulation, or in theform of an intermediate release formulation. In yet other embodiments,the composition is administered topically.

The compound of Formula (I), or a pharmaceutically acceptable saltthereof, may be effective over a wide dosage range. For example, in thetreatment of adult humans, dosages from 0.01 to 1000 mg per day, from0.5 to 100 mg per day, from 1 to 50 mg per day, and from 5 to 40 mg perday are examples of dosages that may be used in some embodiments. Theexact dosage will depend upon the route of administration, the form inwhich the compound is administered, the subject to be treated, the bodyweight of the subject to be treated, and the preference and experienceof the attending physician.

In some embodiments, a compound or salt of Formula (I) is administeredin a single dose. Typically, such administration will be by injection,e.g., intravenous injection, in order to introduce the agent quickly.However, other routes are used as appropriate. In some embodiments, asingle dose of a compound or salt of Formula (I) is used for treatmentof an acute condition.

In some embodiments, a compound or salt of Formula (I) is administeredin multiple doses. In some embodiments, dosing is about once, twice,three times, four times, five times, six times, or more than six timesper day. In other embodiments, dosing is about once a month, once everytwo weeks, once a week, or once every other day. In another embodiment,a compound or salt of Formula (I) and another agent are administeredtogether about once per day to about 6 times per day. In anotherembodiment, the administration of a compound or salt of Formula (I) andan agent continues for less than about 7 days. In yet anotherembodiment, the administration continues for more than about 6 days,more than about 10 days, more than about 14 days, more than about 28days, more than about two months, more than about six months, or oneyear or more. In some cases, continuous dosing is achieved andmaintained as long as necessary.

Administration of a compound or salt of Formula (I) may continue as longas necessary. In some embodiments, a compound of the disclosure isadministered for more than 1, more than 2, more than 3, more than 4,more than 5, more than 6, more than 7, more than 14, or more than 28days. In some embodiments, a compound of the disclosure is administered28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 daysor less, 4 days or less, 3 days or less, 2 days or less, or 1 day or apart thereof. In some embodiments, a compound or salt of Formula (I) isadministered chronically on an ongoing basis, e.g., for the treatment ofchronic effects.

In some embodiments, a compound or salt of Formula (I) is administeredin dosages. It is known in the art that due to intersubject variabilityin compound pharmacokinetics, individualization of dosing regimen isnecessary for optimal therapy. Dosing for a compound or salt of Formula(I) may be found by routine experimentation in light of the instantdisclosure.

In some embodiments, a compound or salt of Formula (I) is formulatedinto pharmaceutical compositions. In specific embodiments,pharmaceutical compositions are formulated in a conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Anypharmaceutically acceptable techniques, carriers, and excipients areused as suitable to formulate the pharmaceutical compositions describedherein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins 1999).

Provided herein are pharmaceutical compositions comprising a compound orsalt of Formula (I) and a pharmaceutically acceptable diluent(s),excipient(s), or carrier(s). In certain embodiments, the compounds orsalts described are administered as pharmaceutical compositions in whicha compound or salt of Formula (I) is mixed with other activeingredients, as in combination therapy. Encompassed herein are allcombinations of active ingredients set forth in the combinationtherapies section below and throughout this disclosure. In specificembodiments, the pharmaceutical compositions include one or morecompounds of Formula (I), or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition, as used herein, refers to a mixture of acompound or salt of Formula (I) with other chemical components, such ascarriers, stabilizers, diluents, dispersing agents, suspending agents,thickening agents, and/or excipients. In certain embodiments, thepharmaceutical composition facilitates administration of the compound toan organism. In some embodiments, practicing the methods of treatment oruse provided herein, therapeutically effective amounts of a compound orsalt of Formula (I) are administered in a pharmaceutical composition toa mammal having a disease, disorder or medical condition to be treated.In specific embodiments, the mammal is a human. In certain embodiments,therapeutically effective amounts vary depending on the severity of thedisease, the age and relative health of the subject, the potency of thecompound used and other factors. A compound or salt of Formula (I) maybe used singly or in combination with one or more therapeutic agents ascomponents of mixtures.

In one embodiment, a compound or salt of Formula (I) is formulated in anaqueous solution. In specific embodiments, the aqueous solution isselected from, by way of example only, a physiologically compatiblebuffer, such as Hank's solution, Ringer's solution, or physiologicalsaline buffer. In other embodiments, a compound or salt of Formula (I)is formulated for transmucosal administration. In specific embodiments,transmucosal formulations include penetrants that are appropriate to thebarrier to be permeated. In still other embodiments wherein a compoundor salt of Formula (I) is formulated for other parenteral injections,appropriate formulations include aqueous or nonaqueous solutions. Inspecific embodiments, such solutions include physiologically compatiblebuffers and/or excipients.

In another embodiment, a compound or salt of Formula (I) is formulatedfor oral administration. A compound or salt of Formula (I) may beformulated by combining the active compounds with, e.g.,pharmaceutically acceptable carriers or excipients. In variousembodiments, a compound or salt of Formula (I) is formulated in oraldosage forms that include, by way of example only, tablets, powders,pills, dragees, capsules, liquids, gels, syrups, elixirs, slurries,suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with a compound or saltof Formula (I), optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipients are,in particular, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as: for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, a therapeutically effective amount of a compoundor salt of Formula (I) is formulated into other oral dosage forms. Oraldosage forms include push-fit capsules made of gelatin, as well as soft,sealed capsules made of gelatin and a plasticizer, such as glycerol orsorbitol. In specific embodiments, push-fit capsules contain the activeingredients in admixture with one or more filler. Fillers include, byway of example only, lactose, binders such as starches, and/orlubricants such as talc or magnesium stearate and, optionally,stabilizers. In other embodiments, soft capsules, contain one or moreactive compound that is dissolved or suspended in a suitable liquid.Suitable liquids include, by way of example only, one or more fatty oil,liquid paraffin, or liquid polyethylene glycol. In addition, stabilizersare optionally added.

In other embodiments, a therapeutically effective amount of a compoundor salt of Formula (I) is formulated for buccal or sublingualadministration. Formulations suitable for buccal or sublingualadministration include, by way of example only, tablets, lozenges, orgels. In still other embodiments, a compound or salt of Formula (I) isformulated for parental injection, including formulations suitable forbolus injection or continuous infusion. In specific embodiments,formulations for injection are presented in unit dosage form (e.g., inampoules) or in multi-dose containers. Preservatives are, optionally,added to the injection formulations. In still other embodiments, thepharmaceutical compositions are formulated in a form suitable forparenteral injection as sterile suspensions, solutions or emulsions inoily or aqueous vehicles. Parenteral injection formulations optionallycontain formulatory agents such as suspending, stabilizing and/ordispersing agents. In specific embodiments, pharmaceutical formulationsfor parenteral administration include aqueous solutions of the activecompounds in water-soluble form. In additional embodiments, a suspensionof a compound or salt of Formula (I) is prepared as appropriate oilyinjection suspensions. Suitable lipophilic solvents or vehicles for usein the pharmaceutical compositions described herein include, by way ofexample only, fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. In certainspecific embodiments, aqueous injection suspensions contain substanceswhich increase the viscosity of the suspension, such as sodiumcarboxymethyl cellulose, sorbitol, or dextran. Optionally, thesuspension contains suitable stabilizers or agents which increase thesolubility of the compounds to allow for the preparation of highlyconcentrated solutions. In certain embodiments, the active agent is inpowder form for constitution with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

In still other embodiments, a compound or salt of Formula (I) isadministered topically. A compound or salt of Formula (I) may beformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compositions optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

In yet other embodiments, a compound or salt of Formula (I) isformulated for transdermal administration. Transdermal formulations mayemploy transdermal delivery devices and transdermal delivery patches andcan be lipophilic emulsions or buffered, aqueous solutions, dissolvedand/or dispersed in a polymer or an adhesive. In various embodiments,such patches are constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. In additional embodiments, thetransdermal delivery of a compound or salt of Formula (I) isaccomplished by means of iontophoretic patches and the like. In certainembodiments, transdermal patches provide controlled delivery of acompound or salt of Formula (I). In specific embodiments, the rate ofabsorption is slowed by using rate-controlling membranes or by trappingthe compound within a polymer matrix or gel. In alternative embodiments,absorption enhancers are used to increase absorption. Absorptionenhancers or carriers include absorbable pharmaceutically acceptablesolvents that assist passage through the skin. For example, in oneembodiment, transdermal devices are in the form of a bandage comprisinga backing member, a reservoir containing a compound or salt of Formula(I), optionally with carriers, optionally a rate controlling barrier todeliver the compound to the skin of the host at a controlled andpredetermined rate over a prolonged period of time, and means to securethe device to the skin.

In other embodiments, a compound or salt of Formula (I) is formulatedfor administration by inhalation. Various forms suitable foradministration by inhalation include, but are not limited to, aerosols,mists or powders. Pharmaceutical compositions of a compound or salt ofFormula (I) are conveniently delivered in the form of an aerosol spraypresentation from pressurized packs or a nebuliser, with the use of asuitable propellant (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In specific embodiments, the dosage unit of apressurized aerosol is determined by providing a valve to deliver ametered amount. In certain embodiments, capsules and cartridges of, suchas, by way of example only, gelatin for use in an inhaler or insufflatorare formulated containing a powder mix of a compound or salt of Formula(I) and a suitable powder base such as lactose or starch.

In still other embodiments, a compound or salt of Formula (I) isformulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas, containing conventional suppository bases such as cocoa butteror other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients may be optionally used as suitable.Pharmaceutical compositions comprising a compound or salt of Formula (I)are manufactured in a conventional manner, such as, by way of exampleonly, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and a compound or salt ofFormula (I), sometimes referred to herein as an active agent oringredient. The active ingredient may be in free-acid or free-base form,or in a pharmaceutically acceptable salt form. Additionally, a compoundor salt of Formula (I) may be in unsolvated or solvated forms withpharmaceutically acceptable solvents such as water and ethanol. Inaddition, the pharmaceutical compositions optionally include othermedicinal or pharmaceutical agents, carriers, adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure, buffers, and/orother therapeutically valuable substances.

Methods for the preparation of compositions comprising a compound orsalt of Formula (I) include formulating the compounds with one or moreinert, pharmaceutically acceptable excipients or carriers to form asolid, semi-solid or liquid. Solid compositions include, but are notlimited to, powders, tablets, dispersible granules, capsules, cachets,and suppositories. Liquid compositions include solutions in which acompound is dissolved, emulsions comprising a compound, or a solutioncontaining liposomes, micelles, or nanoparticles comprising a compoundor salt of Formula (I). Semi-solid compositions include, but are notlimited to, gels, suspensions and creams. The form of the pharmaceuticalcompositions of a compound or salt of Formula (I) include liquidsolutions or suspensions, solid forms suitable for solution orsuspension in a liquid prior to use, or as emulsions. These compositionsalso optionally contain minor amounts of nontoxic, auxiliary substances,such as wetting or emulsifying agents, pH buffering agents, and soforth.

In some embodiments, a pharmaceutical composition comprising a compoundor salt of Formula (I) takes the form of a liquid where the agents arepresent in solution, in suspension or both. Typically when thecomposition is administered as a solution or suspension a first portionof the agent is present in solution and a second portion of the agent ispresent in particulate form, in suspension in a liquid matrix. In someembodiments, a liquid composition includes a gel formulation. In otherembodiments, the liquid composition is aqueous.

In certain embodiments, aqueous suspensions contain one or more polymersas suspending agents. Polymers include water-soluble polymers such ascellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Certain pharmaceutical compositions described herein comprisea mucoadhesive polymer, selected for example fromcarboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally, include solubilizingagents to aid in the solubility of a compound described herein. The term“solubilizing agent” generally includes agents that result in formationof a micellar solution or a true solution of the agent. Certainacceptable nonionic surfactants, for example polysorbate 80, are usefulas solubilizing agents, as can ophthalmically acceptable glycols,polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Pharmaceutical compositions optionally include one or more pH adjustingagents or buffering agents, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Pharmaceutical compositions optionally include one or more preservativesto inhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical compositions may include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Pharmaceutical compositions may include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In certain embodiments, delivery systems for hydrophobic pharmaceuticalcompounds are employed. Liposomes and emulsions are examples of deliveryvehicles or carriers useful herein. In certain embodiments, organicsolvents such as N-methylpyrrolidone are also employed. In additionalembodiments, a compound or salt of Formula (I) is delivered using asustained-release system, such as semipermeable matrices of solidhydrophobic polymers containing the therapeutic agent. Varioussustained-release materials may be used herein. In some embodiments,sustained-release capsules release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

In some embodiments, the concentration of a compound or salt of Formula(I) provided in a pharmaceutical compositions is less than about: 100%,90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%,13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%,0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of a compound or salt of Formula(I) provided in a pharmaceutical composition is greater than about: 90%,80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%,18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%,16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%,13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%,11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%,9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%,6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%,3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%,0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%,0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%,0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of a compound or salt of Formula(I) is in the range from approximately 0.0001% to approximately 50%,approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of a compound or salt of Formula(I) is in the range from approximately 0.001% to approximately 10%,approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of a compound or salt of Formula (I) isequal to or less than about: 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g,7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g,2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g,0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g,0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of a compound or salt of Formula (I) ismore than about: 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g,0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more compounds of thedisclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g,0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes a compound or salt of Formula(I), optionally in a composition or in combination with another agent asdisclosed herein. The container(s) optionally have a sterile access port(for example the container is an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle). Such kitsoptionally comprising a compound with an identifying description orlabel or instructions relating to its use in the methods describedherein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical composition is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack, for example, contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Methods

The present disclosure provides a method of inhibiting the interactionof menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusionprotein, or an MLL Partial Tandem Duplication) comprising contacting acell with an effective amount of a compound or salt of Formula (I).Inhibition of the interaction of menin and one or more proteins (e.g.,MLL1, MLL2, an MLL fusion protein, or an MLL Partial Tandem Duplication)can be assessed and demonstrated by a wide variety of ways known in theart. Non-limiting examples include a showing of (a) a decrease in meninbinding to one or more proteins or protein fragments (e.g., MLL1, MLL2,an MLL fusion protein, an MLL Partial Tandem Duplication, or a peptidefragment thereof); (b) a decrease in cell proliferation and/or cellviability; (c) an increase in cell differentiation; (d) a decrease inthe levels of downstream targets of MLL1, MLL2, an MLL fusion protein,and/or an MLL Partial Tandem Duplication (e.g., Hoxa9, DLX2, PBX3, andMeis1); and/or (e) decrease in tumor volume and/or tumor volume growthrate. Kits and commercially available assays can be utilized fordetermining one or more of the above.

The disclosure also provides methods of using the compounds orpharmaceutical compositions of the present disclosure to treat diseaseconditions, including but not limited to conditions implicated by menin,MLL, MLL1, MLL2, and/or MLL fusion proteins (e.g., cancer).

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering an effective amount of any of theforegoing pharmaceutical compositions comprising a compound or salt ofFormula (I) to a subject in need thereof. In some embodiments, thecancer is mediated by an MLL fusion protein. In other embodiments, thecancer is leukemia, breast cancer, prostate cancer, pancreatic cancer,lung cancer, liver cancer, skin cancer, or a brain tumor. In certainembodiments, the cancer is leukemia. In some embodiments, the cancercomprises a solid tumor.

In some embodiments, the disclosure provides a method of treating adisorder in a subject in need thereof, wherein the method comprisesdetermining if the subject has an MLL fusion protein and, if the subjectis determined to have an MLL fusion protein, administering to thesubject a therapeutically effective dose of a compound or salt ofFormula (I).

MLL fusion proteins have also been identified in hematologicalmalignancies (e.g., cancers that affect blood, bone marrow and/or lymphnodes). Accordingly, certain embodiments are directed to administrationof a compound or salt of Formula (I) to a patient in need of treatmentof a hematological malignancy. Such malignancies include, but are notlimited to leukemias and lymphomas. For example, the presently disclosedcompounds can be used for treatment of diseases such as Acutelymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronicmyelogenous leukemia (CML), Acute monocytic leukemia (AMoL), hairy cellleukemia, and/or other leukemias. In other embodiments, the compoundsare can be used for treatment of lymphomas such as all subtypes ofHodgkins lymphoma or non-Hodgkins lymphoma.

Determining whether a tumor or cancer comprises an MLL fusion proteincan be undertaken by assessing the nucleotide sequence encoding the MLLfusion protein, by assessing the amino acid sequence of the MLL fusionprotein, or by assessing the characteristics of a putative MLL fusionprotein.

Methods for detecting an MLL fusion protein nucleotide sequence areknown by those of skill in the art. These methods include, but are notlimited to, polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) assays, polymerase chain reaction-single strandconformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCRsequencing, mutant allele-specific PCR amplification (MASA) assays,direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. In some embodiments, the MLL fusion protein is identifiedusing a direct sequencing method of specific regions (e.g., exon 2and/or exon 3) in the MLL or fusion partner gene, for example. Thistechnique will identify all possible mutations in the region sequenced.

Methods for detecting an MLL fusion protein are known by those of skillin the art. These methods include, but are not limited to, detection ofan MLL fusion protein using a binding agent (e.g., an antibody) specificfor the fusion protein, protein electrophoresis and Western blotting,and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises an MLLfusion protein can use a variety of samples. In some embodiments, thesample is taken from a subject having a tumor or cancer. In someembodiments, the sample is taken from a subject having a cancer ortumor. In some embodiments, the sample is a fresh tumor/cancer sample.In some embodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

The disclosure also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to the mammal atherapeutically effective amount of a compound or salt of Formula (I).In some embodiments, the method relates to the treatment of cancer suchas acute myeloid leukemia, cancer in adolescents, adrenocorticalcarcinoma childhood, AIDS-related cancers (e.g., Lymphoma and Kaposi'sSarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid,basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, or Viral-Induced cancer. In some embodiments, the methodrelates to the treatment of a non-cancerous hyperproliferative disordersuch as benign hyperplasia of the skin (e.g., psoriasis), restenosis, orprostate (e.g., benign prostatic hypertrophy (BPH)). In some cases, themethod relates to the treatment of leukemia, hematologic malignancy,solid tumor cancer, prostate cancer (e.g., castration-resistant prostatecancer), breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, livercancer (e.g., hepatocellular carcinoma), or diabetes. In some cases, theleukemia comprises AML, ALL, Mixed Lineage Leukemia or leukemias withPartial Tandem Duplications of MLL.

In certain particular embodiments, the disclosure relates to methods fortreatment of lung cancers, the methods comprise administering aneffective amount of any of the above described compound (or apharmaceutical composition comprising the same) to a subject in needthereof. In certain embodiments the lung cancer is a non-small cell lungcarcinoma (NSCLC), for example adenocarcinoma, squamous-cell lungcarcinoma or large-cell lung carcinoma. In other embodiments, the lungcancer is a small cell lung carcinoma. Other lung cancers treatable withthe disclosed compounds include, but are not limited to, glandulartumors, carcinoid tumors and undifferentiated carcinomas.

In some embodiments, a method for treatment of a hematologicalmalignancy or Ewing's sarcoma is provided, the method comprisingadministering an effective amount of any of the foregoing pharmaceuticalcompositions comprising a compound or salt of Formula (I) to a subjectin need thereof.

The hematological condition may be any condition or disease whichprimarily affects the blood. Hematological malignancies include, but arenot limited to, malignant lymphoma (such as lymphoma NOS, microglioma,non-Hodgkin lymphoma NOS, B cell lymphoma NOS, malignant lymphoma,(non-cleaved cell NOS and diffuse NOS), malignant lymphoma (lymphocyticintermediate differentiation nodular, small cell noncleaved diffuse,undifferentiated cell non-Burkitt, and undifferentiated cell type NOS),lymphosarcoma (NOS and diffuse), reticulum cell sarcoma (NOS anddiffuse), reticulosarcoma (NOS and diffuse), composite Hodgkin andnon-Hodgkin lymphoma); leukemia (such as acute myeloid leukemia (AML),acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML)), mixedlineage leukemia (MLL), blast cell leukemia, undifferentiated leukemia,stem cell leukemia, acute leukemia of ambiguous lineage, acute mixedlineage leukemia, acutel bilineal leukemia, chronic lymphocytic leukemia(CLL), chronic myelomonocytic leukemia (CMML), lymphocytic leukemia,lymphatic leukemia); mature B cell neoplasms (such as B-cell chroniclyphocytic leukemia (BCLL)/small cell lymphoma, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma,hairy cell leukemia (HCL), plasma cell myeloma, plasmacytoma, monoclonalimmunoglobulin deposition diseases, heavy chain diseases, marginal zoneB cell lymphoma, lymphoplasmacytic lymphoma, immunocytoma, malignantlymphoma plasmacytoid, plasmacytic lymphoma, nodal marginal zone B celllymphoma, follicular lymphoma (grade 1, 2 or 3), primary cutaneousfollicle center lymphoma, diffuse large B-cell lymphoma (DLBCL), diffuselarge B-cell immunoblastic NOS lymphoma, Epstein-Barr virus-positiveDLBCL of the elderly, lymphomatoid granulomatosis, mantle zone lymphoma,primary mediastinal large B-cell lymphoma, intravascular large B-celllymphoma, plasmablastic lymphoma, primary effusion lymphoma, largeB-cell lymphoma arising in HHV8-associated multicentric Castleman'sdisease, and Burkitt lymphoma/leukemia); mature T cell and naturalkiller (NK) cell neoplasms (such as T-cell prolymphocytic leukemia(T-PLL), T-cell large granular lymphocytic leukemia, aggressive NK cellleukemia, mature T-cell leukemia/lymphoma, extranodal NK/T-cell nasaltype lymphoma, intestinal T-cell lymphoma, enteropathy-associated T-celllymphoma, hepatosplenic T-cell lymphoma, hepatosplenic T-cell ymphoma,blastic NK cell lymphoma, mycosis fungoides or Sezary syndrome, primarycutaneous CD30-positive T cell lymphoproliferative disorders, anaplasticlarge cell lymphoma (T-cell and null cell types), peripheralnon-specific T-cell lymphoma, angioimmunoblastic T-cell lymphoma,anaplastic large cell lymphoma, cutaneous T-cell lymphoma, andsubcutaneous panniculitis-like T-cell lymphoma); precursor lymphoidneoplasms (such as non-specific precursor B-lymphoblasticleukemia/lymphoma, B-lymphoblastic leukemia/lymphoma with recurrentgenetic abnormalities, precursor cell lymphoblastic lymphoma, andprecursor T-lymphoblastic leukemia/lymphoma); Hodgkin lymphoma (HL)(such as classical Hodgkin lymphoma, nodular sclerosis form HL, Hodgkinparagranuloma, Hodgkin ranuloma, mixed cellularlity HL, nodularsclerosis cellular phase HL, lymphocyte-rich HL, nodular sclerosis grade1 HL, nodular sclerosis grade 2 HL lymphocyte depleted HL,lyphocytic-histiocytic predominance HL, miexed cellularity NOS HL,lymphocyte depleted diffuse fibrosis HL, lymphocyte depleted reticularHL, lymphocyte predominance diffuse HL, and nodularlymphocyte-predominant HL); plasma cell tumors (such as plasmacytoma,multiple myeloma (MM), plasma cell leukemia, and plasmacytomaextramedullary); mast cell tumors (such as mastocytoma, mast cellsarcoma, malignant mastocytosis, and mast cell leukemia); neoplasms ofhistiocytes and accessory lymphoid cells (such as malignanthistiocytosis, Langerhans cell histiocytosis (NOS, unifocal, multifocal,or disseminated), histiocytic sarcoma, Langerhans cell sarcoma,dendritic cell sarcoma, and follicular dendritic cell sarcoma);immunoproliferative diseases (such as Waldenstrom macroglobulinemia,heavy chain disease, immunoproliferative small intestinal disease,monoglonal gammopathy of undetermined significance, angiocentricimmunoproliferative lesion, angioimmunoblastic lymphadenopathy, T-gammalymphoproliferative disease, and immunoglobulin deposition disease);myeloid leukemias (such as erythroleukemia, acute myeloid leukemia (NOS,with abnormal marrow eosinophils, minimally differentiated, multilineagedysplasia without maturation, or with maturation), lymphosarcoma cellleukemia, myeloid leukemia NOS, chronic myeloid leukemia NOS, acutepromyelocytic leukemia, FAB-M3, acute myelomonocytic leukemia,basophilic leukemia, chronic myelogenous leukemia (BCR/ABL positive,BCR/ABL negative or atypical), acute monoblastic and monocytic leukemia,chloroma or myeloid sarcoma, acute panmyelosis with myelofibrosis); andmyelodysplastic syndromes (MDS) (such as polycythemia vera, essentialthrombocythemia, myelofibrosis, refractory anemia, (with ringedsideroblasts or excess blasts), and refractory cytopenia withmultilineage dysplasia).

The present disclosure further provides a method of treating ahematological malignancy, such as acute myeloid leukemia, in a subjectexhibiting a nucleoporin 98 (NUP98) gene fusion, mutation in thenucleophosmin (NPM1) gene, mutation in the DNA(cytosine-5)-methyltransferase 3A (DNMT3A) gene, mutation in theFMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitratedehydrogenase 1 (IDH1) gene, mutation in the isocitrate dehydrogenase 2(IDH2) gene, or mixed lineage leukemia (MLL) gene amplification, themethod comprising administering to said subject a compound or salt ofFormula (I). In some embodiments, the present disclosure provides amethod of treating a hematological malignancy, such as acute myeloidleukemia or acute lymphoblastic leukemia, in a subject exhibiting an MLLrearrangement, optionally wherein the subject further exhibits elevatedMEIS1 expression levels, the method comprising administering to saidsubject a compound or salt of Formula (I). In some embodiments, thesubject exhibits a partial tandem duplication of MLL (MLL-PTD). In someembodiments, the present disclosure provides a method of treatingEwing's sarcoma, comprising administering to a subject in need thereof acompound or salt of Formula (I).

In some embodiments, the subject being treated has been tested for thepresence of a genetic abnormality or mutation. In some cases, thesubject has been tested for the presence of a nucleoporin 98 (NUP98)gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in theDNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, mutation in theFMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitratedehydrogenase 1 (IDH1) gene, mutation in the isocitrate dehydrogenase 2(IDH2) gene, or mixed lineage leukemia (MLL) gene amplification. In somecases, the subject has been tested for elevated MEIS1 expression, MLLrearrangement, or partial tandem duplication of MLL. A wide variety ofnucleic acid samples and analyses are available for such testing. Anucleic acid sample may be obtained from the subject. In some cases, thenucleic acid sample comprises a nucleic acid selected from genomic DNA,cDNA, circulating tumor DNA, cell-free DNA, RNA, and mRNA. A biologicalsample may be obtained from the subject. In some cases, the biologicalsample is a tissue sample (e.g., fixed, paraffin-embedded, fresh, orfrozen tissue sample). The tissue sample may be derived from fineneedle, core, or other types of biopsy. In some cases, the biologicalsample is whole blood or plasma.

In some embodiments, a nucleic acid analysis may be conducted on thebiological sample containing nucleic acid. Non-limiting examples of anucleic acid analysis include PCR, sequencing, hybridization,microarray, SNP, cell-free nucleic acid analysis, and whole genomesequencing.

The subject may exhibit a nucleoporin 98 (NUP98) gene fusion. In somecases, the nucleoporin 98 (NUP98) gene fusion is a gene fusion of NUP98and a homeodomain partner gene. In some cases, the nucleoporin 98(NUP98) gene fusion is a gene fusion of NUP98 and a non-homeodomainpartner gene. In some cases, the nucleoporin 98 (NUP98) gene fusion is agene fusion of NUP98 and a partner gene selected from HOXA9, HOXA11,HOXA13, HOXC11, HOXC13, HOXD11, HOXD13, PMX1, PMX2, HHEX, PHF23,JARID1A, NSD1, NSD3, MLL, SETBP1, LEDGF, CCDC28, HMGB3, IQCG, RAP1GDS1,ADD3, DDX10, TOP1, TOP2B, LNP1, RARG, ANKRD28, and POU1F1.

The subject may exhibit a mutation in the nucleophosmin (NPM1) gene. Insome cases, the mutation in the nucleophosmin (NPM1) gene is a mutationin exon 12 of the NPM1 gene. In some cases, the mutation in thenucleophosmin (NPM1) gene is a frameshift mutation. In some cases, themutation in the nucleophosmin (NPM1) gene comprises an insertion of twoto nine bases, such as the insertion is of four bases (e.g., TCTG, CATG,CCTG, CGTG, CAGA, CTTG, and TATG). In some cases, the insertion is ofnine bases (e.g., CTCTTGCCC and CCCTGGAGA). In some cases, the mutationin the nucleophosmin (NPM1) gene comprises a deletion of nucleotides 965through 969 (GGAGG).

The subject may exhibit a mutation in the FLT3 gene. In some cases, themutation in the FLT3 gene is an internal tandem duplication (FLT3-ITD).In some cases, the mutation in the FLT3 gene is an in-frame, internaltandem duplication mutation of a nucleotide sequence within exon 14. Thesize of the FLT3-ITD mutation may range from 3 to over 400 bp. In somecases, the FLT3-ITD mutation is near residues 590-600 of the FLT3 aminoacid sequence. The FLT3-ITD mutation may be located in exon 14, exon 15and/or in the intron between exons 14 and 15. The subject may compriseboth partial tandem duplication of the MLL gene and a FLT3-ITD mutation.The subject may exhibit a FLT3 activating mutation. In some cases, themutation in the FLT3 gene is a point mutation involving the tyrosinekinase domain. In some cases, the mutation of the FLT3 gene is a pointmutation at aspartate 835 or isoleucine 836.

The subject may exhibit a mutation in the DNA(cytosine-5)-methyltransferase 3A (DNMT3A) gene. In some cases, themutation in the DNMT3A gene is a mutation of R882. In some cases, themutation in the DNMT3A gene is not a mutation of R882. In some cases,the mutation in the DNMT3A gene is a frameshift deletion, missensemutation, nonsense mutation, splice-site substitution, splice-sitedeletion, or whole-gene deletion.

The subject may exhibit a mutation in the isocitrate dehydrogenase 1(IDH1) gene or isocitrate dehydrogenase 2 (IDH2) gene. In some cases,the mutation in the isocitrate dehydrogenase 1 (IDH1) gene is aheterozygous somatic point mutation in codon 132. In some cases, themutation in the isocitrate dehydrogenase 2 (IDH2) gene is a heterozygoussomatic point mutation in codons 172 or 140. In some embodiments, themutation in the isocitrate dehydrogenase 2 (IDH2) gene is R140Q.

The subject may exhibit one or more of an NPM1 mutation, FLT3 mutation,IDH1 mutation, IDH2 mutation, and DNMT3A mutation. In some cases, thesubject exhibits an NPM1 mutation, a FLT3 mutation, an IDH2 mutation anda DNMT3A mutation. In some cases, the subject exhibits an NPM1 mutation,an IDH1 mutation, a FLT3 mutation and a DNMT3A mutation. In some cases,the subject exhibits an NPM1 mutation, a FLT3 mutation and a DNMT3Amutation. In some cases, the subject exhibits an NPM1 mutation, a FLT3mutation and an IDH1 mutation. In some cases, the subject exhibits anNPM1 mutation, a FLT3 mutation and an IDH2 mutation. In some cases, thesubject exhibits an NPM1 mutation, a DNMT3A mutation and an IDH1mutation. In some cases, the subject exhibits an NPM1 mutation, a DNMT3Amutation and an IDH2 mutation. In some cases, the subject exhibits anNPM1 mutation and a FLT3 mutation.

The subject may exhibit a mixed lineage leukemia (MLL) geneamplification. The subject may exhibit a mixed lineage leukemia (MILL)gene rearrangement. The subject may exhibit an 11q23 rearragement. Thesubject may exhibit MLL partial tandem duplications.

The subject may exhibit an EWSR1-FLI1 gene fusion, EWSR1-ERG genefusion, or EWSR1-FEV gene fusion. The subject may exhibit a FUS-NCATc2gene fusion, CIC-FOXO4 gene fusion, or ETV6-NTRK3 gene fusion. Thesubject may exhibit a mutation in a STAG2 gene, mutation in a TP53 gene,or CDKN2A deletion.

The subject may exhibit elevated myeloid ecotropic viral integrationsite 1 homolog (MEIS1) expression levels (MEIS1^(high)). As used herein,“expression” refers to the process by which a polynucleotide istranscribed into mRNA and/or the process by which the transcribed mRNA(also referred to as a “transcript”) is subsequently translated intopeptides, polypeptides, or proteins. The transcripts and the encodedpolypeptides are collectedly referred to as “gene product.” If thepolynucleotide is derived from genomic DNA, expression may includesplicing of the mRNA in a eukaryotic cell. The level of expression (oralternatively, the “expression level”) of a MEIS1 gene can bedetermined, for example, by determining the level of MEIS1polynucleotides, polypeptides, and/or gene products. “Differentiallyexpressed” or “differential expression” as applied to a nucleotidesequence (e.g., a gene) or polypeptide sequence in a subject, refers tothe differential production of the mRNA transcribed and/or translatedfrom the nucleotide sequence or the protein product encoded by thenucleotide sequence. A differentially expressed sequence may beoverexpressed or underexpressed as compared to the expression level of areference sample (i.e., a reference level). As used herein, elevatedexpression levels refer to an increase in expression, generally at least1.25 fold, or alternatively, at least 1.5 fold, or alternatively, atleast 2 fold, or alternatively, at least 3 fold, or alternatively, atleast 4 fold, or alternatively, at least 10 fold expression over thatdetected in a reference sample. As used herein, underexpression is areduction in expression and generally is at least 1.25 fold, oralternatively, at least 1.5 fold, or alternatively, at least 2 fold, oralternatively, at least 3 fold, or alternatively, at least 4 fold, oralternatively, at least 10 fold expression under that detected in areference sample. Underexpression also encompasses absence of expressionof a particular sequence as evidenced by the absence of detectableexpression in a test subject when compared to a reference sample.

Determining whether a tumor or cancer comprises a nucleoporin 98 (NUP98)gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in theDNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, mutation in theFMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitratedehydrogenase 1 (IDH1) gene, mutation in the isocitrate dehydrogenase 2(IDH2) gene, or mixed lineage leukemia (MLL) gene amplification can beundertaken by assessing the nucleotide sequence encoding the protein, byassessing the amino acid sequence of the protein, or by assessing thecharacteristics of a putative protein.

Determining whether a tumor or cancer comprises an MLL rearrangement orpartial tandem duplication of MLL (MLL-PTD) can be undertaken byassessing the nucleotide sequence encoding the protein, by assessing theamino acid sequence of the protein, or by assessing the characteristicsof a putative protein.

Determining whether a tumor or cancer comprises elevated MEIS1expression levels can be assessed by any appropriate method. Theexpression level of a gene, such as MEIS1, may be assessed by detectinga level of mRNA transcribed from the gene, by detecting a level of cDNAproduced from reverse transcription of mRNA transcribed from the gene,by detecting a level of polypeptide encoded by the gene, or by a nucleicacid amplification assay, a hybridization assay, sequencing, or acombination thereof. Regulation of a target gene or gene transcript canalso be determined indirectly, such as by measuring the effect on aphenotypic indicator of the gene or gene transcript activity, such as bycellular assay. Methods of detecting gene expression products are knownin the art. These methods can be performed on a sample by sample basisor modified for high throughput analysis, for example, using Affymetrix™U133 microarray chips.

Methods for detecting a nucleotide sequence of a nucleoporin 98 (NUP98)gene fusion, mutation in the nucleophosmin (NPM1) gene, mutation in theDNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene, mutation in theFMS-like tyrosine kinase-3 (FLT3) gene, mutation in the isocitratedehydrogenase 1 (IDH1) gene, mutation in the isocitrate dehydrogenase 2(IDH2) gene, or mixed lineage leukemia (MLL) gene amplification areknown by those of skill in the art. Similarly, methods for detecting anMLL rearrangement, elevated MEIS1 expression levels, or partial tandemduplication of MLL (MLL-PTD) are known by those of skill in the art.These methods include, but are not limited to, polymerase chainreaction-restriction fragment length polymorphism (PCR-RFLP) assays,polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP) assays, real-time PCR assays, PCR sequencing, mutantallele-specific PCR amplification (MASA) assays, direct sequencing,primer extension reactions, electrophoresis, oligonucleotide ligationassays, hybridization assays, TaqMan assays, SNP genotyping assays, highresolution melting assays and microarray analyses. In some embodiments,the NUP98 fusion protein is identified using a direct sequencing methodof specific regions in the NUP98 or fusion partner gene, for example. Insome embodiments, the mutation in the nucleophosmin (NPM1) gene,mutation in the DNA (cytosine-5)-methyltransferase 3A (DNMT3A) gene,mutation in the FMS-like tyrosine kinase-3 (FLT3) gene, mutation in theisocitrate dehydrogenase 1 (IDH1) gene, mutation in the isocitratedehydrogenase 2 (IDH2) gene, or mixed lineage leukemia (MLL) geneamplification is identified using a direct sequencing method of specificregions in the gene, for example. This technique can identify allpossible mutations in the region sequenced.

Methods for detecting an NUP98 fusion protein, mutant nucleophosmin(NPM1) protein, mutant FMS-like tyrosine kinase-3 (FLT3) protein, mutantisocitrate dehydrogenase 1 (IDH1) protein, mutant isocitratedehydrogenase 2 (IDH2) protein, or mutant DNA(cytosine-5)-methyltransferase 3A (DNMT3A) protein are known by those ofskill in the art. These methods include, but are not limited to,detection of a mutant protein or fusion protein, such as an NUP98 fusionprotein, using a binding agent (e.g., an antibody) specific for themutant protein or fusion protein, protein electrophoresis and Westernblotting, and direct peptide sequencing.

Subjects that can be treated with a compound of the disclosure, or apharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,stereoisomer, isotopologue, hydrate or derivative of the compound,according to the methods of this disclosure include, for example,subjects that have been diagnosed as having acute myeloid leukemia,acute myeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma),anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, viral-induced cancer, leukemia, hematologic malignancy,solid tumor cancer, prostate cancer, castration-resistant prostatecancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma,hepatocellular carcinoma, liver cancer, or diabetes. In some embodimentssubjects that are treated with the compounds of the disclosure includesubjects that have been diagnosed as having a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The disclosure further provides methods of modulating the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein,or an MLL Partial Tandem Duplication) by contacting the menin with aneffective amount of a compound or salt of Formula (I). Modulation can beinhibiting or activating protein activity of menin, one or more of itsbinding partners, and/or one or more of the downstream targets of meninor one or more of its binding partners. In some embodiments, thedisclosure provides methods of inhibiting the interaction of menin andone or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLLPartial Tandem Duplication) by contacting menin with an effective amountof a compound or salt of Formula (I). In some embodiments, thedisclosure provides methods of inhibiting the interaction of menin andone or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLLPartial Tandem Duplication) by contacting a cell, tissue, or organ thatexpresses menin, MLL1, MLL2, an MLL fusion protein, and/or an MLLPartial Tandem Duplication. In some embodiments, the disclosure providesmethods of inhibiting protein activity in subject including but notlimited to rodents and mammal (e.g., human) by administering to thesubject an effective amount of a compound or salt of Formula (I). Insome embodiments, the percentage modulation exceeds 25%, 30%, 40%, 50%,60%, 70%, 80%, or 90%. In some embodiments, the percentage of inhibitingexceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%.

In some embodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in a cell bycontacting the cell with an amount of a compound of the disclosuresufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in the cell. In some embodiments, the disclosure providesmethods of inhibiting the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in a tissue by contacting the tissue with an amount of acompound or salt of Formula (I) sufficient to inhibit the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein,or an MLL Partial Tandem Duplication) in the tissue. In someembodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in an organism bycontacting the organism with an amount of a compound or salt of Formula(I) sufficient to inhibit the interaction of menin and one or moreproteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLL PartialTandem Duplication) in the organism. In some embodiments, the disclosureprovides methods of inhibiting the interaction of menin and one or moreproteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLL PartialTandem Duplication) in an animal by contacting the animal with an amountof a compound of the disclosure sufficient to inhibit the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein,or an MLL Partial Tandem Duplication) in the animal. In someembodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in a mammal bycontacting the mammal with an amount of a compound of the disclosuresufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in the mammal. In some embodiments, the disclosure providesmethods of inhibiting the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in a human by contacting the human with an amount of acompound of the disclosure sufficient to inhibit the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein,or an MLL Partial Tandem Duplication) in the human. The presentdisclosure provides methods of treating a disease mediated by theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in a subject inneed of such treatment.

The disclosure also provides methods of treating a disorder mediated bymenin interaction with one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) by administeringto a subject in need thereof a therapeutically effective amount of acompound or salt of Formula (I).

The disclosure further provides methods of treating a disorder mediatedby chromosomal rearrangement on chromosome 11q23 in a subject in needthereof by administering to the subject a therapeutically effectiveamount of a compound or salt of Formula (I).

The disclosure also provides methods for the treatment of a disease orcondition by administering an effective amount of a compound or salt ofFormula (I) to a subject suffering from the disease or condition.

The disclosure further provides methods for the treatment of a diseaseor condition by administering a compound or salt of Formula (I) to asubject suffering from the disease or condition, wherein the compoundbinds to menin and inhibits the interaction of menin with one or moreproteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLL PartialTandem Duplication).

The disclosure further provides methods of stabilizing menin, comprisingcontacting menin with a compound or salt of Formula (I). In someembodiments, the contacting step comprises contacting menin with anamount of the compound sufficient to stabilize menin. In someembodiments, the contacting step takes place in vivo. In someembodiments, the contacting step takes place in vitro. In someembodiments, the contacting step takes place in a cell.

The present disclosure also provides methods for combination therapiesin which an agent known to modulate other pathways, or other componentsof the same pathway, or even overlapping sets of target enzymes are usedin combination with a compound or salt of Formula (I). In one aspect,such therapy includes but is not limited to the combination of one ormore compounds of the disclosure with chemotherapeutic agents,therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

Where desired, a compound or pharmaceutical composition of the presentdisclosure can be used in combination with Notch inhibitors and/or c-Mybinhibitors. Where desired, a compound or pharmaceutical composition ofthe present disclosure can be used in combination with MLL-WDR5inhibitors and/or Dot11 inhibitors. Where desired, a compound orpharmaceutical composition of the present disclosure can be used incombination with FLT3 inhibitors and/or Dot1L inhibitors. In someembodiments, a compound or pharmaceutical composition of the presentdisclosure is administered in combination with a second therapeutic thatis effective in treating subjects that exhibit a FLT3 mutation, such asFLT3-ITD, or who otherwise exhibit oncogenic FLT3. In some embodiments,a compound or pharmaceutical composition of the present disclosure isadministered in combination with a FLT3 inhibitor, such as quizartinib.Exemplary FLT3 inhibitors include quizartinib (AC220), crenolanibbesylate (CP-868596-26), gilteritinib (ASP2215), lestaurtinib (CEP-701),midostaurin (Rydapt®, PKC412), pexidartinib (PLX3397), ponatinib(AP24534), SKLB1028, sorafenib (Nexavar®), sunitinib (Sutent®, SU11248),and XL999. In some embodiments, a compound or pharmaceutical compositionof the present disclosure is administered in combination with as IDH2inhibitor such as enasidenib.

Many chemotherapeutics are presently known in the art and can be used incombination with a compound of the disclosure. In some embodiments, thechemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK®; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentdisclosure can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

This disclosure further relates to a method for using a compound or saltof Formula (I) or a pharmaceutical composition provided herein, incombination with radiation therapy for inhibiting abnormal cell growthor treating the hyperproliferative disorder in the mammal. Techniquesfor administering radiation therapy are known in the art, and thesetechniques can be used in the combination therapy described herein. Theadministration of the compound of the disclosure in this combinationtherapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present disclosure include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

The compounds or pharmaceutical compositions of the disclosure can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the disclosure and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24,1996), WO 96/27583 (published Mar. 7,1996), European PatentApplication No. 97304971.1 (filed Jul. 8,1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26,1998), WO 98/03516 (published Jan. 29,1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13,1994),European Patent Publication 931, 788 (published Jul. 28,1999), WO90/05719 (published May 31,1990), WO 99/52910 (published Oct. 21,1999),WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun.17,1999), PCT International Application No. PCT/IB98/01113 (filed Jul.21,1998), European Patent Application No. 99302232.1 (filed Mar.25,1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999),U.S. Pat. No. 5,863,949 (issued Jan. 26,1999), U.S. Pat. No. 5,861,510(issued Jan. 19,1999), and European Patent Publication 780,386(published Jun. 25, 1997), all of which are incorporated herein in theirentireties by reference. Preferred MMP-2 and MMP-9 inhibitors are thosethat have little or no activity inhibiting MMP-1. More preferred, arethose that selectively inhibit MMP-2 and/or AMP-9 relative to the othermatrix-metalloproteinases (e.g., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6,MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specificexamples of MMP inhibitors useful in the disclosure are AG-3340, RO32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen ornedocromil; anti-infectives, e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments are used inthe form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) or as solvates(e.g., hydrates) to optimize the activity and/or stability of themedicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, Mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the disclosure include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentdisclosure with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present disclosure withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentdisclosure with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present disclosure with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present disclosure with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

Further therapeutic agents that can be combined with a compound of thedisclosure are found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the disclosure will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein are administered with the second agent simultaneouslyor separately. This administration in combination can includesimultaneous administration of the two agents in the same dosage form,simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of thedisclosure and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentdisclosure can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the disclosure and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

The present disclosure provides a method of promoting beta cellproliferation. In some embodiments, the method comprises contactingmenin with an effective amount of a compound of Formula (I). Optionally,the compound inhibits the interaction of menin and MLL. Inhibition ofthe menin/MLL interaction can be assessed by a wide variety oftechniques known in the art. Non-limiting examples include a showing of(a) a decrease in menin binding to MLL, or a peptide fragment thereof;(b) a decrease in p27^(Kip1) and/or p18^(INK4C) mRNA levels; (c) adecrease in p27^(Kip1) and/or p18^(INK4C) protein levels; (d) a decreasein the levels of downstream targets of MLL; (e) an increase in betacells; and/or (f) an increase in pancreatic islet cell proliferation.Kits and commercially available assays can be utilized for determiningone or more of the above. In some embodiments, the promoted beta cellproliferation is evidenced by an increase in insulin production.Optionally, contacting menin comprises contacting a cell that expressesmenin. The contacting step may take place in vivo or in vitro. Thepromoted beta cell proliferation may be evidenced by an increase in betacell production. In some embodiments, the number of beta cells in atreated islet increases by at least 1.1-fold, at least 1.2-fold, atleast 1.3-fold, at least 1.4-fold, at least 1.5-fold, at least 1.6-fold,at least 1.7-fold, at least 1.8-fold, at least 1.9-fold, at least2-fold, at least 2.5-fold, at least 3-fold, at least 4-fold, at least5-fold, at least 7.5-fold, or at least 10-fold relative to the number ofbeta cells in an islet treated with vehicle only. In some embodiments,the increase in the number of beta cells in a treated islet is comparedto a number of beta cells in an islet prior to treatment. Beta cellproliferation may be assessed using methods known in the art. Forexample, beta cell proliferation can be assessed usingquantitative-stereological methods or by immunohistochemistry imagingmethods, either using manual or automated image processing. Non-limitingexamples of suitable methods are described in Noorafshan, A.; et al. J.Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.

In certain embodiments, the present disclosure provides a method ofincreasing the size of a pancreatic islet, comprising administering aneffective amount of a compound described herein to a subject in needthereof. In some embodiments, the average size of treated pancreaticislets increases by at least 5%, at least 10%, at least 15%, at least20%, at least 25%, at least 30%, at least 35%, at least 40%, at least45%, at least 50%, at least 55%, or at least 60% relative to the averagesize of pancreatic islets treated with vehicle only. The size ofpancreatic islets may be expressed in any unit commonly used in the art,such as area (e.g., mm²) or volume (e.g., mm³), and can be assessedusing methods known in the art. For example, pancreatic islet size canbe assessed using quantitative-stereological methods or byimmunohistochemistry imaging methods, either using manual or automatedimage processing. Non-limiting examples of suitable methods aredescribed in Noorafshan, A.; et al. J. Pancreas 2012, 13, 427-432; Chen,H.; et al. Frontiers in Physiology 2013, 3, 1-9; and Kilimnik, G.; etal. Islets 2012, 4, 167-172.

In certain embodiments, the present disclosure provides a method ofincreasing the average beta cell number per islet, comprisingadministering an effective amount of a compound described herein to asubject in need thereof. In some embodiments, the average beta cellnumber per islet of treated islets increases by at least 5%, at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, or at least 40% relative to the average beta cell number per isletof islets treated with vehicle only. The average beta cell number perislet can be assessed using methods known in the art. For example,average beta cell number per islet can be assessed usingquantitative-stereological methods or by immunohistochemistry imagingmethods, either using manual or automated image processing. Non-limitingexamples of suitable methods are described in Noorafshan, A.; et al. J.Pancreas 2012, 13, 427-432; Chen, H.; et al. Frontiers in Physiology2013, 3, 1-9; and Kilimnik, G.; et al. Islets 2012, 4, 167-172.

In certain embodiments, the present disclosure provides a method ofimproving islet transplantation, comprising contacting an islet cellwith an effective amount of a compound described herein. In someembodiments, the contacting takes place prior to transplantation of theislet into a recipient. In some embodiments, the contacting takes placeafter transplantation of the islet into a recipient. The contacting maytake place in vivo, ex vivo or in vitro.

In certain embodiments, the present disclosure provides a method oftreating a disease or condition in a subject having impaired beta cellproduction, comprising administering to the subject an effective amountof a compound of Formula (I). The disease or condition may comprisediabetes, such as type 1 diabetes or type 2 diabetes. In someembodiments, the disease or condition is characterized by impairedglucose metabolism and/or hyperglycemia. The treated subject may exhibitdecreased plasma glucose levels. For example, plasma glucose levels maybe reduced by at least 10 mg/dL, 20 mg/dL, 30 mg/dL, 40 mg/dL, 50 mg/dL,60 mg/dL, 70 mg/dL, 80 mg/dL, 90 mg/dL, or at least 100 mg/dL relativeto plasma glucose levels measured before the administering the effectiveamount of the compound of Formula (I). A fasting plasma glucose level ofthe treated subject may be less than 150 mg/dL, such as less than 140mg/dL, 130 mg/dL, 120 mg/dL, 110 mg/dL, 100 mg/dL, 90 mg/dL, or lessthan 80 mg/dL.

In certain embodiments, the present disclosure provides a method oftreating impaired glucose metabolism, comprising administering aneffective amount of a compound or salt of Formula (I) to a subject inneed thereof.

Subjects that can be treated according the subject methods include, forexample, subjects that have been diagnosed as having impaired glucosetolerance, hyperglycemia, impaired glucose metabolism, diabetes, type 1diabetes, or type 2 diabetes, or subjects suffering from a diseaseassociated with reduced beta cell number and/or impaired beta-cellfunction, for example but not limited to one of the diseases for which apro-proliferative effect on pancreatic beta cells and/or ananti-apoptotic/pro-survival effect on pancreatic beta cells and/or abeta cell neogenesis-promoting effect would be beneficial: Type Idiabetes: new onset, established, prevention in high-risk patients(identified e.g. via screening for multiple autoantibodies); LADA: newonset and established; Type II diabetes: when loss of beta cell massoccurs; MODY (Maturity Onset Diabetes of the Young, all forms);Gestational diabetes; Islet+duct cell transplantation-treatment ofrecipients before or after transplantation; Treatment of islets beforetransplantation/during pre-transplantation culture; andPancreatitis-associated beta cell loss.

The methods described herein may be used to treat diabetes type I, LADAor prognosed diabetes type II, but also used preventively on subjects atrisk to develop complete beta-cell degeneration, like for example butnot limited to patients suffering from diabetes type II or LADA and typeI diabetes in early stages, or other types of diseases as indicatedabove. The methods may also be used to prevent or ameliorate diabetes inpatients at risk for type I diabetes or LADA (identified e.g. byscreening for autoantibodies, genetic predisposition, impaired glucosetolerance or combinations thereof.

The following examples are given for the purpose of illustrating variousembodiments of the disclosure and are not meant to limit the presentdisclosure in any fashion. The present examples, along with the methodsand compositions described herein, are presently representative ofpreferred embodiments, are exemplary, and are not intended aslimitations on the scope of the disclosure. Changes therein and otheruses which are encompassed within the spirit of the disclosure asdefined by the scope of the claims will occur to those skilled in theart.

EXAMPLES Example 1

Synthesis of4-((2S)-1-(2-cyano-4-methyl-5-((7-(2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indol-1-yl)propan-2-yl)-N-methylpiperazine-1-sulfonamide(1).

4-((2S)-1-(2-cyano-4-methyl-5-((7-(2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indol-1-yl)propan-2-yl)-N-methylpiperazine-1-sulfonamide(1) is synthesized in nine steps starting from 4,4,4-trifluorobutanaland 2-cyanoacetamide.

Example 2

Synthesis of5-((7-(2-amino-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-4-methyl-1-((S)-2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile(2).

5-((7-(2-amino-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-4-methyl-1-((S)-2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile(2) is synthesized in six steps starting from tert-butyl7-(2-chloro-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonane-2-carboxylate(1-4) from Example 1.

Example 3

Synthesis ofN-(3-((2-cyano-4-methyl-5-((7-(2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)propionamide(3).

N-(3-((2-cyano-4-methyl-5-((7-(2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)-1H-indol-1-yl)methyl)bicyclo[1.1.1]pentan-1-yl)propionamide(3) is synthesized in six steps starting from methyl3-((tert-butoxycarbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (3-1).

Example 4

Synthesis ofN-((1r,4r)-4-((7-(2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)methanesulfonamide(4).

N-((1r,4r)-4-((7-(2-methyl-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)methyl)cyclohexyl)methanesulfonamide(4) is synthesized in three steps starting from2-methyl-4-(2,7-diazaspiro[4.4]nonan-2-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidine(1-6).

Example 5

Synthesis of Compound 25.

Step A: To a solution of compound 5-1 (2.2 g, 10.0 mmol) and1,1,1-trimethoxyethane (6 mL, 50.0 mmol) in 15 mL of toluene was added200 mg of TsOH. The reaction was stirred at 130° C. overnight. Solventwas removed to give the crude product, which was purified by silica gelcolumn chromatography (eluent: DCM/MeOH=40:1) to give compound 5-2 as abrown solid (2.2 g, yield: 98%).

Step B: To a mixture of compound 5-2 (500 mg, 2.2 mmol) in 10 mL ofPOCl₃ was added PCl₅ (937 mg. 4.5 mmol), and the reaction was stirred at120° C. for 10 hours. Solvent was removed and the residue was dilutedwith DCM. The organic solution was washed with NaHCO₃, H₂O, brine anddried over Na₂SO₄. The solution was filtered and concentrated. Theresidue was purified by silica gel column chromatography (eluent:PE/EA=5:1) to give compound 5-3 as a brown oil (500 mg, yield: 98%).

Step C: A mixture of compound 5-3 (1.6 g, 6 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (1.3 g, 6 mmol) and DIEA (1.56g, 12 mmol) in 30 mL of THF was stirred at 60° C. for 10 hours. Solventwas removed and the residue was diluted with EA. The organic solutionwas washed with NaHCO₃, H₂O, brine and dried over Na₂SO₄. The solutionwas filtered and concentrated. The residue was purified by silica gelcolumn chromatography (eluent: PE/EA=5:1-3:1) to give compound 1-5 (1.6g, yield: 59%). ESI-MS m/z: 457.40 (M+H) ¹HNMR (400 MHz, CDCl₃) δ:7.28(s, 1H), 3.92-3.96 (m, 2H), 3.34-3.80 (m, 8H), 2.57 (s, 3H), 1.91-2.10(m, 4H), 1.48 (s, 9H).

Step D: To a solution of compound 1-5 (180 mg, 0.27 mmol) in 4 mL of DCMwas added 3 mL of TFA and the reaction mixture was stirred at roomtemperature for 3 hours. Solvent was removed and 10 mL of 7N NH₃ in MeOHsolution was added. Solvent was removed and the residue was purified bysilica gel column chromatography (eluent: 10% MeOH in DCM) to givecompound 1-6 as a yellow solid (1.3 g, yield: 100%). ESI-MS m/z: 357.35(M+H).

Step E: To a mixture of compound 5-4 (1.5 g, 10 mmol) and Et₃N (2.0 g,20 mmol) in 10 mL of DCM was add slowly MsCl (1.4 g, 12 mmol) at 0° C.under N₂. The reaction mixture was stirred at room temperature for 18 hbefore it was diluted with DCM. The organic solvent was washed withNaHCO₃, H₂O, brine and dried over Na₂SO₄. The solution was filtered andconcentrated. The residue was purified by silica gel columnchromatography (eluent: PE/EA=1:1) to give compound 5-5 as a white solid(500 mg, yield: 20%).

Step F: To a mixture of compound 5-5 (500 mg, 2.0 mmol) in 10 mL of THFwas add slowly LAH (80 mg, 2.0 mmol) at 0° C. under N₂. The mixture wasstirred at room temperature for 1 h, and additional LAH (80 mg, 2.0mmol) was added at 0° C. The reaction was quenched with EA, H₂O, and 1NHCl. Solid was filtered and the organic solvent was concentrated. Theresidue was purified by silica gel column chromatography (eluent:DCM/MeOH=20:1) to give compound 5-6 as a white solid (230 mg, yield:55%).

Step G: To a solution of compound 5-6 (230 mg, 1.1 mmol) and in 10 mL ofTHF was add slowly MnO₂ (200 mg, 2.2 mmol). The mixture was stirred at60° C. under N₂ for 8 h. The mixture was filtered and the organicsolvent was concentrated. Compound 5-7 was obtained after silica gelcolumn chromatography (eluent: PE/EA=5:1) as a brown solid (200 mg,yield: 90%).

Step H: A solution of compound 5-7 (60 mg, 0.27 mmol), compound 1-6 (90mg, 0.25 mmol) and TEA (150 mg, 1.5 mmol) in 15 mL of DCM was stirred atroom temperature for 2 hours before NaBH(OAc)₃ (320 mg, 1.5 mmol) wasadded. The mixture reaction was stirred at room temperature overnight.The reaction was partitioned between DCM and NaHCO₃ (sat.), and theorganic layer was washed by brine and dried over Na₂SO₄. The solvent wasremoved under vacuum and the residue was purified by Prep-TLC(DCM/MeOH=20:1) to give compound 25 as a solid (60 mg, yield: 40%).ESI-MS m/z: 540.12 (M+H). ¹HNMR (400 MHz, DMSO): 9.66 (s, 1H), 7.63 (s,1H), 7.19-7.30 (dd, 4H, J=8.8 Hz), 4.04 (q, J=10.4 Hz, 2H), 3.50-3.95(m, 6H), 2.96 (s, 3H), 2.40-2.65 (m, 4H), 2.42 (s, 3H), 1.78-2.05 (m,4H).

Example 6

Synthesis of Compound 11.

Step A: A solution of compound 1-3 (3.20 g, 11.15 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (2.52 g, 11.15 mmol) and DIEA(2.88 g, 22.3 mmol) in 80 mL of THF was stirred at 50° C. overnight.Solvent was removed under vacuum and the residue was dissolved in ethylacetate. The solution was washed with saturated NaHCO₃ aqueous solutionand brine, dried with anhydrous sodium sulfate and purified by silicagel column chromatography (PE/EA: 3/1) to give compound 1-4 as a solid(4.5 g, yield: 85%). ESI-MS m/z: 476 (M+H).

Step B: A mixture of compound 1-4 (1.24 g, 2.6 mmol), TEA (1.6 g, 13mmol) and CH₃NH₂ alcohol solution (1.78 g, 13 mmol) was added to a sealtube and stirred at 100° C. overnight. Solvent was removed and theresidue was purified by silica gel column chromatography (PE/EA:3/1-1:1) to give compound 6-1 as a solid (1.21 g, 98%). ESI-MS m/z: 472(M+H).

Step C: To a solution of compound 6-1 (0.5 g, 1.06 mmol) in 8 mL of DCMwas added 2 mL of TFA. The mixture was stirred at room temperature for 3h. DCM and TFA were removed under vacuum and the residue was dissolvedin MeOH and 7N MeOHNH₃ was added. Then MeOH was removed under vacuum andthe residue was purified by silica gel column chromatography (DCM/MeOH:10/1) to give compound 6-2 as a solid (0.37 g, 94%). ESI-MS m/z: 372.2(M+H).

Step D: A solution of compound 6-2 (73 mg, 0.197 mmol), compound 3-4 (75mg 0.197 mmol) and TEA (119.2 mg, 1.18 mmol) in 10 mL of DCM was stirredat room temperature for 2 h before NaBH(OAc)₃ (250 mg, 1.18 mmol) wasadded slowly and stirred overnight. The reaction solution was washedwith saturated NaHCO₃ aqueous solution, brine, and dried with anhydroussodium sulfate. Solvent was removed and the residue was purified bysilica gel column chromatography (DCM/MeOH: 30/1) to give compound 6-3as a solid (130 mg, 89%). ESI-MS m/z: 368.45 (M+H).

Step E: To a solution of compound 6-3 (130 mg, 0.177 mmol) in 3 mL ofDCM, was added 3 mL of TFA. The mixture was stirred at room temperaturefor 3 h. DCM and TFA were removed under vacuum and the residue wasdissolved in MeOH and MeOH NH₃ was added to neutralize the TFA residue.Then MeOH was removed under vacuum and residue was purified by silicagel column chromatography (DCM/MeOH: 30/1) to give compound 6-4 as asolid (86 mg, 76%). ESI-MS m/z: 635.25 (M+H).

Step F: A mixture of compound 6-4 (86 mg, 0.136 mmol), propionic acid(21 mg, 0.272 mmol), and BOP (115 mg, 0.272 mmol) was dissolved in 15 mLDCM and stirred for 20 minutes before DIEA (53 mg, 0.41 mmol) was addedand stirred overnight. The reaction solution was washed with water,saturated NaHCO₃ aqueous solution, dried with anhydrous sodium sulfateand purified with silica gel column chromatography (10% MeOH indichloromethane) to give final product 11 as a solid (40 mg, 42%).ESI-MS m/z: 691.30 (M+H). ¹HNMR (400 MHz, DMSO): 8.22 (s, 1H), 7.55 (m,1H), 7.3-7.42 (m, 2H), 6.5 (s, 1H), 4.49 (s, 2H), 3.85 (m, 3H),3.50-3.80 (m, 6H), 2.78 (m, 3H), 2.5-2.7 (m, 8H), 1.89-2.06 (m, 5H),1.70 (m, 6H), 0.85-0.95 (m, 3H).

Example 7

Synthesis of Compound 26.

A solution of compound 5-7 (40 mg, 0.2 mmol), compound 6-2 (75 mg, 0.2mmol) and TEA (120 mg, 1.2 mmol) in 15 mL of DCM was stirred at roomtemperature for 2 hours before NaBH(OAc)₃ (255 mg, 1.2 mmol) was added.The reaction mixture was stirred at room temperature overnight. Thereaction mixture was partitioned between DCM and NaHCO₃ (sat.), and theorganic layer was washed by brine and dried over Na₂SO₄. Solvent wasremoved under vacuum to get a residue, which was purified byPrep-TLC(DCM/MeOH=15:1) to give 26 as a solid (40 mg, yield: 36%).ESI-MS m/z: 555.18 (M+H). ¹HNMR (400 MHz, DMSO): 9.72 (br, 1H),7.16˜7.40 (m, 5H), 4.86 (d, J=4.8 Hz, 1H), 3.86 (q, J=10.8 Hz, 2H),3.14˜3.72 (m, 8H), 2.98 (s, 3H), 2.78 (d, J=4.4 Hz, 3H), 2.50˜2.70 (m,2H), 1.68˜2.00 (m, 4H).

Example 8

Synthesis of Compound 17.

A solution of compound 8-1 (104 mg, 0.28 mmol), compound 1-6 (100 mg,0.28 mmol) and TEA (170 mg, 1.7 mmol) in 15 mL of DCM was stirred atroom temperature for 2 hours before NaBH(OAc)₃ (360 mg, 1.7 mmol) wasadded. The mixture reaction was stirred at room temperature overnight.The reaction mixture was partitioned between DCM and NaHCO₃ (sat.), andthe organic layer was washed by brine and dried over Na₂SO₄. The solventwas removed under vacuum to get a residue, which was purified by silicagel column chromatography (eluent: DCM/MeOH=20:1) plus a secondpurification by Prep-HPLC to give 17 as a solid (80 mg, yield: 30%).ESI-MS m/z: 728.1 (M+H), 364.5 (½ M+H). ¹HNMR (400 MHz, DMSO): 7.61 (s,1H), 7.47 (m, 1H), 7.30˜7.36 (m, 2H), 3.97˜4.30 (m, 4H), 3.60˜3.72 (m,6H), 2.97˜3.15 (m, 3H), 2.88 (s, 3H), 2.50˜2.67 (m, 3H), 2.34˜2.46 (m,5H), 1.58˜2.16 (m, 8H), 0.96 (d, J=6.4 Hz, 3H), 0.80˜0.88 (m, 3H).

Example 9

Synthesis of Compound 30.

Step A: To a solution of compound 9-1 (2.0 g, 10.0 mmol) in 15 mL of DCMwas added 2-aminoethanol (3 ml, 30 mmol) at room temperature. Thereaction was stirred overnight. Solvent was removed to give the crudeproduct, which was purified by silica gel column chromatography (eluent:DCM/MeOH=40:1) to give compound 9-2 as a yellow solid (2.3 g, yield:98%).

Step B: A mixture of compound 9-2 (2.3 g, 10 mmol) in DCM was added DHP(1.26 g, 15 mmol), followed by TsOH (172 mg, 1 mmol). The reactionmixture was stirred at room temperature for 10 hours, and diluted withDCM. The organic solvent was washed with NaHCO₃ (sat.), H₂O, brine anddried over Na₂SO₄. The solution was filtered and concentrated and theresidue was purified by silica gel column chromatography (elutedPE/EA=1:1) to give compound 9-3 as a yellow solid (3.5 g, yield: 98%).

Step C: To a solution of compound 9-3 (3.5 g, 10 mmol) in 35 mL of MeOHwas added 300 mg of Pd/C. The reaction was stirred at room temperatureunder H₂ for 10 hours. The suspension was filtered and concentrated togive compound 9-4 as a brown solid (2.5 g, yield: 85%).

Step D: To a mixture of compound 9-4 (2.5 g, 8.5 mmol) and DIEA (3.4 g,27 mmol) in 30 mL of MeCN was added CDI (2.1 g, 13 mmol) at roomtemperature. The reaction mixture was stirred at 60° C. for 8 h, thendiluted with ethyl acetate. The organic solution was washed with H₂O,brine and dried over Na₂SO₄. The solution was filtered and concentrated.The residue was purified by silica gel column chromatography (elutedPE/EA=1:1) to give compound 9-5 as a white solid (2.6 g, yield: 90%).

Step E: To a mixture of compound 9-5 (2.5 g, 7.8 mmol) in THF (30 mL)was added slowly LAH (1.2 g, 31 mmol) at 0° C. under N₂. The reactionmixture was stirred at room temperature for 4 h. The reaction wasquenched with ethyl acetate, H₂O, and 2N NaOH. Solid was filtered andthe organic solvent was concentrated. The residue was purified by silicagel column chromatography (eluent: DCM/MeOH=20:1) to give compound 9-6as a brown solid (1.7 g, yield: 75%).

Step F: To a solution of compound 9-6 (1.7 g, 5.8 mmol) in 30 mL of THFwas added slowly MnO₂ (1.1 g, 11.7 mmol). The reaction mixture wasstirred at 60° C. under N₂ for 8 h. The mixture was filtered and theorganic solvent was concentrated. The product compound 9-7 was obtainedafter flash column chromatography (eluent: DCM/MeOH=50:1) purificationas a brown solid (1.5 g, yield: 90%).

Step G: A solution of compound 9-7 (60 mg, 0.2 mmol), compound 6-2 (75mg, 0.2 mmol) and TEA (120 mg, 1.2 mmol) in 15 mL of DCM was stirred atroom temperature for 2 hours before NaBH(OAc)₃ (255 mg, 1.2 mmol) wasadded. The reaction mixture was stirred at room temperature overnight.The reaction mixture was partitioned between DCM and NaHCO₃ (sat.), andthe organic layer was washed by brine and dried over Na₂SO₄. The solventwas removed under vacuum to get the residue, which was purified byPrep-TLC (DCM/MeOH=20:1) to give compound 9-8 as a solid (100 mg, yield:75%). ESI-MS m/z: 646.12 (M+H).

Step H: To a solution of compound 9-8 (100 mg, 0.27 mmol) in 4 mL of DCMwas added 3 mL of TFA and the reaction mixture was stirred at roomtemperature for 3 hours. Solvent was removed and a solution of 7N NH₃ inMeOH (10 ml) was added. Solvent was removed and the residue was purifiedby Prep-TLC (eluted DCM/MeOH=12:1) to give 30 as a solid (50 mg, yield:45%). ESI-MS m/z: 562.3 (M+H)¹HNMR (400 MHz, DMSO): 10.80 (br, 1H), 7.38(s, 1H), 6.95˜7.08 (m, 3H), 6.50 (m, 1H), 4.86 (t, J=5.6 Hz, 1H),3.55˜4.10 (m, 12H), 3.05˜3.30 (m, 2H), 2.78 (d, J=4.8 Hz, 3H), 2.54˜2.72(m, 2H), 1.70˜2.10 (m, 4H).

Example 10

Synthesis of Compound 5.

Step A: A solution of compound 6-2 (70 mg, 0.189 mmol), compound 1-7 (66mg 0.160 mmol) and TEA (114 mg, 1.13 mmol) in 10 mL of DCM was stirredfor 2 h before NaBH(OAc)₃ (240 mg, 1.13 mmol) was added slowly andstirred overnight. Then the reaction solution was washed with saturatedNaHCO₃ aqueous solution, brine, and dried with anhydrous sodium sulfate.Solvent was removed and the residue was purified by silica gel columnchromatography (DCM/MeOH: 30/1) to give compound 10-1 as a solid (128mg, 88%). ESI-MS m/z: 384, 766.5(M+H).

Step B: To a solution of compound 10-1 (128 mg, 0.167 mmol) in 3 mL ofDCM was added 3 mL of TFA. The mixture was stirred at room temperaturefor 3 h. DCM and TFA were removed under vacuum and the residue wasdissolved in MeOH before MeOH.NH₃ was added to neutralize the TFAresidue. MeOH was removed under vacuum to give crude compound 10-2 as asolid (120 mg). ESI-MS m/z: 666 (M+H).

Step C: To a solution of compound 10-2 (110 mg, 0.167 mmol) and TEA (33mg, 0.25 mmol) in DCM (10 mL) at −10° C. was added methylsulfamoylchloride (33 mg, 0.25 mmol) over 20 mins and stirred at room temperaturefor 1 h. Then 1 mL water was added to quench the reaction, and thesolution was washed with water, saturated NaHCO₃ aqueous solution andbrine and dried with anhydrous sodium sulfate. Solvent was removed andresidue was purified by silica gel column chromatography (DCM/MeOH:10/1) to give the final product 5 as a solid. ESI-MS m/z: 380.7, 759.3(M+H). ¹HNMR (400 MHz, DMSO): 8.22 (d, J=1.6 Hz, 1H), 7.33-7.40 (m, 3H),8.22 (q, J=4.8 Hz, 1H), 6.51 (d, J=4.4 Hz, 1H), 4.13-4.30 (m, 2H),3.50-3.95 (m, 8H), 2.87-3.15 (m, 6H), 2.50-2.80 (m, 8H), 2.45-2.50 (m,3H), 2.30-2.34 (m, 2H), 1.78-2.10 (m, 5H), 0.98 (d, J=6.4 Hz, 3H),0.80-0.86 (m, 2H).

Example 11

Synthesis of Compound 44.

Step A: A mixture of compound 11-1 (0.5 g, 2 mmol), tert-butyl2,7-diazaspiro[4.4]nonane-2-carboxylate (450 mg, 2 mmol) and DIEA (516mg, 4 mmol) in 10 mL of THF was stirred at 60° C. for 10 hours. Solventwas removed by vacuum and the residue was diluted with ethyl acetate.The solution was filtered and concentrated. The residue was purified bysilica gel column chromatography (eluent: PE/EA-5:1-3:1) to givecompound 11-2 as a yellow solid (800 mg, yield: 90%). ESI-MS m/z: 443.40(M+H).

Step B: To a solution of compound 11-2 (500 mg, 1.1 mmol) in 4 mL of DCMwas added 2 mL of TFA and the reaction solution was stirred at roomtemperature for 3 hours. Solvent was removed and a solution of 7N NH₃ inMeOH (10 ml) was added. Solvent was evaporated and the residue purifiedby silica gel column chromatography (eluent: 10% MeOH indichloromethane) to give compound 11-3 as a yellow solid (400 mg, yield:100%).

Step C: To a suspension of t-BuOK (10 g, 89.5 mmol) in 70 mL of t-AmOHwas added compound 11-4 (6 g, 35.8 mmol) in 150 mL of t-AmOH dropwise atroom temperature over 2 h.

The reaction mixture was stirred for another 1 h before MeOH (50 mL) andwater (5 mL) were added and stirred for 30 mins. The mixture wasconcentrated under vacuum to dryness and the residue was purified bysilica gel column chromatography (EA/MeOH: 20/1) to give compound 11-5as a solid (0.85 g, 18%). ¹H NMR (400 MHz, DMSO) δ:7.95 (s, 1H), 4.86(t, 1H), 4.01 (m, 2H), 3.65 (m, 1H), 3.37˜3.55 (m, 2H), 3.03˜3.23 (m,2H). ESI-MS m/z: 345. 3 (M+H).

Step D: Compound 11-5 (600 mg, 2.28 mmol) and compound 11-6 (840 mg,2.28 mmol) were dissolved in 100 mL of THF and stirred for 20 mins. Thereaction solution cooled below −10° C. before Ph₃P (1.57 mg, 3.42 mmol)in 15 mL of THF was added dropwise over 40 mins and stirred for 20 mins.Then DBAD (1.79 g, 3.42 mmol) in 15 mL of THF was added dropwise over 30mins and the resulting mixture was stirred at room temperatureovernight. Solvent was removed and the residue and purified by silicagel column chromatography (PE/EA 1:1˜0:1) to give compound 11-7 as asolid (300 mg, 44.3%). ESI-MS m/z: 298.50 (M+H). ¹H NMR (400 MHz, DMSO)δ: 10.38 (m, 1H), 8.0˜8.13 (m, 1H), 7.40˜7.88 (m, 2H), 7.67˜7.76 (m,1H), 4.6˜4.7 (m, 1H), 4.4˜4.5 (m, 1H), 4.0˜4.13 (m, 2H), 3.88˜4.0 (m,1H), 3.38˜3.47 (m, 1), 3.12˜3.22 (t, 1H), 2.8˜2.9 (m, 3H).

Step E: A solution of compound 11-7 (30 mg, 0.101 mmol), compound 11-3(43 mg 0.119 mmol) and TEA (72 mg, 0.713 mmol) in 16 mL of DCM wasstirred for 2 h before NaBH(OAc)₃ (151 mg, 0.713 mmol) was added slowlyand stirred overnight. Then the reaction solution was washed withsaturated NaHCO₃ aqueous solution, brine, and dried with anhydroussodium sulfate. Solvent was removed and residue was purified by silicagel column chromatography (DCM/MeOH: 10/1) to give 44 as a solid (30 mg,46%). ESI-MS m/z: 623.25 (M+H). ¹HNMR (400 MHz, DMSO): 8.26 (s, 1H),8.05 (d, 1H), 7.60˜7.70 (s, 2H), 7.40˜7.58 (m, 1H), 7.20˜7.40 (s, 1H),4.55 (m, 1H), 4.40 (m, 1H), 3.95˜4.18 (m, 5H), 3.55˜3.74 (m, 4H),3.10˜3.30 (m, 2H), 2.52˜2.80 (m, 5H), 2.30˜2.51 (m, 3H), 1.70˜2.25 (m,5H).

Example 12

Fluorescence Polarization Assay.

This example illustrates an assay effective

in monitoring the binding of MLL to menin. Fluorescence polarization(FP) competition experiments were performed to determine theeffectiveness with which a compound inhibits the menin-MLL interaction,reported as an IC₅₀ value. A fluorescein-labeled peptide containing thehigh affinity menin binding motif found in MLL was produced according toYokoyama et al. (Cell, 2005, 123(2): 207-218), herein incorporated byreference in its entirety. Binding of the labeled peptide (1.7 kDa) tothe much larger menin (˜67 kDa) is accompanied by a significant changein the rotational correlation time of the fluorophore, resulting in asubstantial increase in the fluorescence polarization and fluorescenceanisotropy (excitation at 500 nm, emission at 525 nm). The effectivenesswith which a compound inhibits the menin-MLL interaction was measured inan FP competition experiment, wherein a decrease in fluorescenceanisotropy correlates with inhibition of the interaction and was used asa read-out for IC₅₀ determination.

Table 2 shows biological activities of selected compounds in afluorescence polarization assay. Compound numbers correspond to thenumbers and structures provided in Table 1 and Examples 1-11.

TABLE 2 Less than 50 nM to less than 250 nM to Greater than 50 nM (++++)250 nM (+++) 1000 nM (++) 1000 nM (+) Menin 5, 14, 17, 21, 22, 30, 1, 8,9, 11, 26, 46, 3, 25, 29, 42, 139, 41, 96, 125, 128, MLL 4-43 43, 44,45, 68, 69, 126, 127 152, 155 129, 140, 141, 142, IC₅₀ (nM) 70, 75, 77143, 144, 145, 146, 147, 148, 149, 150, 151, 153, 154, 156, 157, 158,159

Example 13

Homogenous Time-Resolve Fluorescence (HTRF) Assay.

A homogeneous time-resolve fluorescence (HTRF) assay is utilized as asecondary assay to confirm the results of the FP assay. In someembodiments, the HTRF assay is the primary assay and the FP assay isused as a secondary assay to confirm results. HTRF is based on thenon-radiative energy transfer of the long-lived emission from theEuropium cryptate (Eu³⁺-cryptate) donor to the allophycocyanin (XL665)acceptor, combined with time-resolved detection. An Eu³⁺-cryptate donoris conjugated with mouse anti-6His monoclonal antibody (which bindsHis-tagged menin) and XL665-acceptor is conjugate to streptavidin (whichbinds biotinylated MLL peptide). When these two fluorophores are broughttogether by the interaction of menin with the MLL peptide, energytransfer to the acceptor results in an increase in fluorescence emissionat 665 nm and increased HTRF ratio (emission intensity at 665nm/emission intensity at 620 nm). Inhibition of the menin-MLLinteraction separates the donor from the acceptor, resulting in adecrease in emission at 665 nm and decreased HTRF ratio.

Example 14

Cell Proliferation Assay.

The ability of a compound of the present disclosure to inhibit thegrowth of cells, such as human leukemia cell, acute myeloid leukemiacell, cells with an MLL fusion, control cells without an MLL fusion,VCaP, LNCaP, 22RV1, DU145, LNCaP-AR, MV4;11, KOPN-8, ML-2, MOLM-13,RS4;11, SEM, bone marrow cells (BMCs), MLL-AF9, MLL-AF4, MLL-ENL,MLL-CBP, MLL-GAS7, MLL-AFlp, MLL-AF6, HM-2, E2A-HLF, REH, U937, K562,KG-1, HL-60 and NB4 cells, is tested using a cell viability assay, suchas the Promega CellTiter-Glo® Luminescent Cell Viability Assay (PromegaTechnical Bulletin, 2015, “CellTiter-Glo® Luminescent Cell ViabilityAssay”: 1-15, herein incorporated by reference in its entirety). Cellsare plated at relevant concentrations, for example about 1×10⁵-2×10⁵cells per well in a 96-well plate. A compound of the present disclosureis added at a concentration up to about 2 μM with eight, 2-fold serialdilutions for each compound. Cells are incubated at 37° C. for a periodof time, for example, 72 hours, then cells in the control wells arecounted. Media is changed to restore viable cell numbers to the originalconcentration, and compounds are re-supplied. Proliferation is measuredabout 72 hours later using Promega CellTiter-Glo® reagents, as per kitinstructions.

Example 15

RT-PCR Analysis of ILL Fusion Protein Downstream Targets.

The effect of a compound of the present disclosure on expression of oneor more MLL fusion protein downstream targets is assessed by RT-PCR.Cells, such as human leukemia cell, acute myeloid leukemia cell, cellswith an MLL fusion, control cells without an MLL fusion, VCaP, LNCaP,22RV1, DU145, LNCaP-AR, MV4;11, KOPN-8, ML-2, MOLM-13, RS4;11, SEM, bonemarrow cells (BMCs), MLL-AF9, MLL-AF4, MLL-ENL, MLL-CBP, MLL-GAS7,MLL-AF1p, MLL-AF6, HM-2, E2A-HLF, REH, U937, K562, KG-1, HL-60 and NB4cells, are treated with an effective concentration of a compounddisclosed herein for about 7 days or less, then total RNA is extractedfrom cells using any available kit such as an RNeasy mini kit (QIAGEN)according to the manufacturer's instructions. Total RNA is reversetranscribed using a High Capacity cDNA Reverse Transcription Kit(Applied Biosystems), and relative quantification of relevant genetranscripts (e.g., Hoxa9, DLX2, PBX3, and Meis1) is determined byreal-time PCR. Effective inhibition of the menin-MLL interaction isexpected to result in the downregulation of downstream targets of MLL,including Hoxa9, DLX2, PBX3, and Meis1.

Example 16

Pharmacokinetic Studies in Mice.

The pharmacokinetics of menin-MLL inhibitors are determined in femaleC57BL/6 mice following intravenous (iv) dosing at 15 mg/kg and oraldosing (po) at 30 mg/kg. Compounds are dissolved in the vehiclecontaining 25% (v/v) DMSO, 25% (v/v) PEG-400 and 50% (v/v) PBS. Serialblood samples (50 μL) are collected over 24 h, centrifuged at 15,000 rpmfor 10 min and saved for analysis. Plasma concentrations of thecompounds are determined by the LC-MS/MS method developed and validatedfor this study. The LC-MS/MS method consists of an Agilent 1200 HPLCsystem and chromatographic separation of tested compound is achievedusing an Agilent Zorbax Extend-C18 column (5 cm×2.1 mm, 3.5 m; Waters).An AB Sciex QTrap 3200 mass spectrometer equipped with an electrosprayionization source (ABI-Sciex, Toronto, Canada) in the positive-ionmultiple reaction monitoring (MRM) mode is used for detection. Allpharmacokinetic parameters are calculated by noncompartmental methodsusing WinNonlin® version 3.2 (Pharsight Corporation, Mountain View,Calif., USA).

Example 17

Efficacy Study in Mouse Xenograft Tumor Model.

Immunodeficient mice, such as 8-10 week-old female nude (nu/nu) mice,are used for in vivo efficacy studies in accordance with the guidelinesapproved by IACUC. Leukemia cells, such as human MV4-11 leukemia cellsavailable from ATCC, are implanted subcutaneously via needle into femalenude mice (5×10⁶ cells/mouse). When the tumor reaches a size ofapproximately 150 to 250 mm³ in mice, the tumor-bearing mice arerandomly assigned to a vehicle control or compound treatment group (8animals per group). Animals are treated with a compound of the presentdisclosure by oral gavage or intraperitoneal injection in an appropriateamount and frequency as can be determined by the skilled artisan withoutundue experimentation. Subcutaneous tumor volume in nude mice and micebody weight are measured twice weekly. Tumor volumes are calculated bymeasuring two perpendicular diameters with calipers(V=(length×width²)/2). Percentage tumor growth inhibition (%TGI=1−[change of tumor volume in treatment group/change of tumor volumein control group]*100) is used to evaluate anti-tumor efficacy.Statistical significance is evaluated using a one-tailed, two sample ttest. P<0.05 is considered statistically significant.

Example 18

Efficacy Study in Prostate Tumor Xenograft Model.

Immunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. Parental prostatecancer cells, such as VCaP or LNCaP-AR cells, are implantedsubcutaneously into male CB. 17.SCID mice (3-4×10⁶ cells in 50%Matrigel). When the tumor reaches a palpable size of approximately 80mm³, the tumor-bearing mice are randomly assigned to a vehicle controlor compound treatment group (6 or more animals per group). Animals aretreated with a compound of the present disclosure by intraperitonealinjection in an appropriate amount and frequency as can be determined bythe skilled artisan without undue experimentation. In one example, miceare treated with 40 mg/kg of a compound of the present disclosure dailyby i.p. injection for two weeks, then 5 days per week thereafter.Subcutaneous tumor volume and mice body weight are measured twiceweekly. Tumor volumes are calculated by measuring two perpendiculardiameters with calipers (V=(length×width²)/2).

Example 19

Efficacy Study in Castration-Resistant Prostate Tumor Xenograft Model(VCaP).

Immunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. Parental prostatecancer cells, such as VCaP cells, are implanted subcutaneously into maleCB.17.SCID mice (3-4×10⁶ cells in 50% Matrigel). When the tumor reachesa size of approximately 200-300 mm³, the tumor-bearing mice arephysically castrated and tumors observed for regression and regrowth toapproximately 150 mm³. The tumor-bearing mice are randomly assigned to avehicle control or compound treatment group (6 or more animals pergroup). Animals are treated with a compound of the present disclosure byintraperitoneal injection in an appropriate amount and frequency as canbe determined by the skilled artisan without undue experimentation. Inone example, mice are treated with 40 mg/kg of a compound of the presentdisclosure daily by i.p. injection. Subcutaneous tumor volume and micebody weight are measured twice weekly. Tumor volumes are calculated bymeasuring two perpendicular diameters with calipers(V=(length×width²)/2).

Example 20

Efficacy Study in Castration-Resistant Prostate Tumor Xenograft Model(LNCaP-AR).

Immunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. CB. 17. SCID mice aresurgically castrated and allowed to recover for 2-3 weeks beforeimplanting parental prostate cancer cells, such as LNCaP-AR cells,subcutaneously into (3-4×10⁶ cells in 50% Matrigel). When the tumorreaches a size of approximately 80-100 mm³, the tumor-bearing mice arerandomly assigned to a vehicle control or compound treatment group (6 ormore animals per group). Animals are treated with a compound of thepresent disclosure by intraperitoneal injection in an appropriate amountand frequency as can be determined by the skilled artisan without undueexperimentation. In one example, mice are treated with 60 mg/kg of acompound of the present disclosure daily by i.p. injection for 27 days.Subcutaneous tumor volume and mice body weight are measured twiceweekly. Tumor volumes are calculated by measuring two perpendiculardiameters with calipers (V=(length×width²)/2).

Example 21

Cellular Thermal Shift Assay (CETSA).

For the cell lysate CETSA experiments, cultured cells from cell lines(e.g., HEK293, bone marrow samples) are harvested and washed with PBS.The cells are diluted in kinase buffer (KB) (25 mMTris(hydroxymethyl)-aminomethane hydrochloride (Tris-HCl, pH 7.5), 5 mMbeta-glycerophosphate, 2 mM dithiothreitol (DTT), 0.1 mM sodium vanadiumoxide, 10 mM magnesium chloride) or in phosphate-buffered saline (PBS)(10 mM phosphate buffer (pH 7.4), 2.7 mM potassium chloride and 137 mMsodium chloride). All buffers are supplemented with Complete proteaseinhibitor cocktail. The cell suspensions are freeze-thawed three timesusing liquid nitrogen. The soluble fraction (lysate) is separated fromthe cell debris by centrifugation at 20000×g for 20 minutes at 4° C. Thecell lysates are diluted with appropriate buffer and divided into twoaliquots, with one aliquot being treated with drug and the other aliquotwith the diluent of the inhibitor (control). After 10-30 minuteincubation at room temperature the respective lysates are divided intosmaller (50 μL) aliquots and heated individually at differenttemperatures for 3 minutes followed by cooling for 3 minutes at roomtemperature. The appropriate temperatures are determined in preliminaryCETSA experiments. The heated lysates are centrifuged at 20000×g for 20minutes at 4° C. in order to separate the soluble fractions fromprecipitates. The supernatants are transferred to new microtubes andanalyzed by sodium dodecyl sulfate polyacrylamide gel electrophoresis(SDS-PAGE) followed by western blot analysis.

For the intact cell experiments the drug-treated cells from the in vitroexperiments above are heated as previously described followed byaddition of KB (30 μL) and lysed using 2 cycles of freeze-thawing withliquid nitrogen. The soluble fractions are isolated and analyzed bywestern blot.

For the in vivo mice experiments, lysates of frozen tissues are used.The frozen organs (e.g., liver or kidney) are thawed on ice and brieflyrinsed with PBS. The organs are homogenized in cold PBS using tissuegrinders followed by 3 cycles of freeze-thawing using liquid nitrogen.Tissue lysates are separated from the cellular debris and lipids. Thetissue lysates are diluted with PBS containing protease inhibitors,divided into 50 μL aliquots and heated at different temperatures.Soluble fractions are isolated and analyzed by western blot.

It is expected that the aliquots treated with one or more of thecompounds disclosed herein exhibit increased thermal stabilization ofmenin compared to the control aliquots.

Example 22

CETSA-Like Dot-Blot Experiments on Purified Proteins.

Purified protein (0.5 μg) is added to the wells of a PCR plate and thevolume adjusted to 50 μL by addition of buffer or cell lysates andligands depending on the experimental setup. The samples are heated forthe designated time and temperature in a thermocycler. After heating,the samples are immediately centrifuged for 15 min at 3000×g andfiltered using a 0.65 m Multiscreen HTS 96 well filter plate. 3 μL ofeach filtrate are blotted onto a nitrocellulose membrane. Primaryantibody and secondary conjugate are used for immunoblotting. Allmembranes are blocked with blocking buffer; standard transfer andwestern blot protocols recommended by the manufacturers are used. Allantibodies are diluted in blocking buffer. The dot-blot is developed.Chemiluminescence intensities are detected and imaged. Raw dot blotimages are processed. The background is subtracted and intensities arequantified. Graphs are plotted and fitted using sigmoidal dose-response(variable slope).

Example 23

Cell Proliferation Assays.

The ability of a compound of the present disclosure to inhibit thegrowth of cells is tested in both MLL leukemia cell lines (e.g., MV4;11,MOLM13 and/or KOPN8) and control cell lines (e.g., K562, REH, U937,KG-1, and/or HL-60) using the MTT cell proliferation assay (ATCC®30-1010K). Cells are plated at about 1×10⁵ cells per well in a 96-wellplate. A compound of the present disclosure is added at a concentrationup to about 2 μM with seven, 2-fold serial dilutions for each compound.Cells are incubated at 37° C. for 72 hours, then cells in the controlwells were counted. Media is changed to restore viable cell numbers tothe original concentration, and compounds are re-supplied. Proliferationis measured 96 hours later using MTT reagents, as per kit instructions.

Example 24

Efficacy Study in Mouse Xenograft Tumor Model.

Immunocompromised 8-10 week-old female nude (nu/nu) mice are used for invivo efficacy studies in accordance with IACUC guidelines. Human MV4; 11leukemia cells available from ATCC are implanted subcutaneously intofemale nude mice (5×10⁶ cells/mouse). When the tumor reach a size ofapproximately 150 to 250 mm³, the tumor-bearing mice are randomlyassigned to a vehicle control or a compound treatment group (8 mice pergroup). Mice in each treatment group are administered a compound of thepresent disclosure by oral gavage at the dosage indicated (50 mg/kg,bid; 50 gm/kg, qd; 100 mg/kg, bid; 100 mg/kg, qd; 200 mg/kg, qd.; or 200mg/kg, bid). Subcutaneous tumor volume and mouse body weight aremeasured twice weekly. Tumor volumes are calculated by measuring twoperpendicular diameters with calipers (V=(length×width²)/2).

Example 25

Efficacy Study in Xenotransplantation Mouse Model of MLL Leukemia.

Immunocompromised 8-10 week-old female NSG mice are used for in vivoefficacy studies in accordance with IACUC guidelines. Luciferaseexpressing human MV4; 11 leukemia cells (MV4; 11-luc) are engraftedintravenously via tail vein injection (1×10⁷ cells/animal). When themean luminescence of the cells reach approximately 1.5×10⁶, thetumor-bearing mice are randomly assigned to a vehicle control or acompound treatment group (5 animals per group). Animals in each of thetreatment groups are administered a different compound of the presentdisclosure by oral gavage (120 mg/kg b.i.d, 150 mg/kg b.i.d., 200 mg/kgb.i.d., or 200 mg/kg q.d.). Body weight is measured daily, while meanluminescence is measured 6 days after initiating the treatment withcompound or vehicle.

Animals are sacrificed on Day 7 of treatment and bone marrow samplescollected and prepared for gene expression analysis. Expression levelsof MLL fusion protein target genes HOXA9, DLX2, PBX3, and/or MEIS1 aremeasured by qRT-PCR.

Example 26

Survival Study in Xenotransplantation Mouse Model of MLL Leukemia.

For survival studies in the xenotransplantation MV4; 11 xenograft model,6 to 8-week old female NSG mice are intravenously injected with 1×10⁷luciferase-expressing MV4;11 cells harboring MLL-AF4 translocation. Atday 12 after transplantation, treatment is initiated with a compounddisclosed herein and is continued for 22 consecutive days.

For survival studies in the xenotransplantation MOLM13 xenograft model,6 to 8-week old female NSG mice are intravenously injected with 0.5×10⁶MOLM13 cells harboring MLL-AF9 translocation. At day 4 aftertransplantation, treatment is initiated with a compound disclosed hereinand is continued for 16 consecutive days in the compound treated mice oruntil terminal leukemia developed in the vehicle-treated mice.

Example 27

Cell Culture and Islet Isolation.

Islet cells can be isolated from a variety of species according tomethods known in the art. For example, rat islets are isolated by thestandard collagenase digestion method from the pancreata of adultSprague-Dawley rats (200-250 g) and cultured in RPMI medium (Invitrogen)with 10% FBS (Thermo Scientific). In brief, approximately 9 mL ofice-cold Collagenase V (Sigma) solution is injected into the pancreasvia the common bile duct. After dissection, the pancreas is incubatedfor approximately 35 min at about 37° C. and then further dissociated byrepeated pipetting by using a 10-mL pipette. Islets are purified byHistopaque 1.077 (Sigma) density gradient centrifugation and manuallypicked by using a stereomicroscope. Islets are allowed to recover fromthe isolation procedure for an approximate duration of 1-2 days in RPMImedium containing approximately 10% fetal bovine serum in non-tissueculture-treated petri dishes to prevent attachment.

Example 28

Rat Primary Dispersed Islet Cell Proliferation Assay.

Rested islets, such as rat islets, are trypsinized to single-cellsuspensions and plated in 384-well clear bottom plates and cultured inthe presence or absence of a subject compound disclosed herein forapproximately 4 days in growth medium containing approximately 2 μM EdU(Invitrogen). Cells are fixed in 4% paraformaldehyde solution (ElectronMicroscopy Sciences) and stained by standard immunofluorescencetechniques for insulin (polyclonal guinea pig antiinsulin, DAKO) andnuclear DNA is stained with Hoechst. EdU incorporation is measured byclick reaction with AlexaFluor-647-azide (Invitrogen). Plates are imagedon ImageXpress Ultra (Molecular Devices). Imaging data are analyzed byMetaXpress (Molecular Devices). Total insulin positive cells andEdU/insulin-double positive cells are counted and reported as percentageof insulin positive cells containing EdU. Fold change can be calculatedby normalizing percent EdU-positive β cells to DMSO-treated wells.

Example 29

Human Islet Proliferation Assay.

Freshly-isolated explants of non-diabetic, human pancreatic islets arecultured in the presence of DMSO or a compound disclosed herein for 120hours in growth medium containing 10 μM EdU (1000 islet equivalents persample). Islets are fixed and stained by immunofluorescence for insulinand EdU. Beta cell proliferation, islet area, and average beta cellnumber per islet are assessed in accordance with methods describedherein. Treatment with a compound disclosed herein induces beta cellproliferation, as evidenced by an increase in the size of human isletsand/or an increase in the average beta cell number per islet.

Example 30

Human Islet Isolation.

Human islet isolations are conducted using standard procedures in theart, for example, as described in Qi, M. et al. Transplantation Direct2015, 1-9 (doi: 10.1097/TXD.0000000000000522). In short, a donorpancreas is cleaned and cannulated, then subjected to automatedperfusion using a perfusion apparatus. Liberase HI, collagenase NB1 withNP, or liberase MTF C/T is infused, then the distended pancreas is cutinto pieces and loaded into a digestion chamber for digestion at 37° C.Once 50% or more of the islets are free from acinar tissues, the enzymedigestion is terminated by adding surplus media for enzyme dilution.Tissue is collected, centrifuged and combined with human serum albumin.The combined tissue is purified using a cell processor and continuousdensity gradients. After isolations, islets are cultured in ConnaughtMedical Research Laboratories 1066 medium (pH 7.4) with 0.5% human serumalbumin and 0.1 μg/mL insulin-like growth factor-1 at 37° C. under 5%CO₂ for up to 72 hours.

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein may be employed in practicing the invention.It is intended that the following claims define the scope of theinvention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: H is selectedfrom C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; A is

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—; Z⁵ and Z⁶ is independentlyselected from —C(H)— and —N—; B is selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle; C is selected from bond, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle; each of L¹, L², and L³ isindependently selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, and —N(R⁵¹)S(O)N(R⁵¹)— or from alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene, andheteroalkynylene, each of which is optionally substituted with one ormore R⁵⁰, wherein two R⁵⁰ groups attached to the same atom or differentatoms of any one of L¹, L², or L³ can together optionally form a bridgeor ring; R⁵⁰ is, at each occurrence, independently selected from:halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(R⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²); C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵⁰ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁵¹ is independently selected at each occurrence from:hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴; C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂carbocycle and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵¹ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁵² is independently selected at each occurrence fromhydrogen; and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, each of which is optionally substituted by halogen, —CN,—NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂carbocycle, or 3- to 6-membered heterocycle; R⁵³ and R⁵⁴ are takentogether with the nitrogen atom to which they are attached to form aheterocycle, optionally substituted with one or more R⁵⁰; R⁵⁷ isselected from: hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlysubstituted at each occurrence with one or more substituents selectedfrom —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,—NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,—OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and R⁵⁸ is selected from hydrogen; andC₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; R^(A1) is, at each occurrence, independently selected fromhydrogen and R⁵⁰; R^(A2) is, at each occurrence, independently selectedfrom hydrogen and R⁵⁰; each of R^(H) and R^(B) is, at each occurrence,independently selected from R⁵⁰, or two R^(H) groups or two R^(B) groupsattached to the same atom or different atoms can together optionallyform a bridge or ring; R^(C) is, at each occurrence, independentlyselected from hydrogen or R⁵⁰, or two R^(C) groups attached to the sameatom or different atoms can together optionally form a bridge or ring;and each of m, p, and q is independently an integer from 0 to
 12. 2. Acompound of Formula (I-G):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein: H is selected from C₅₋₆ carbocycle and 5- to6-membered heterocycle; H² is selected from C₅₋₆ carbocycle and 5- to6-membered heterocycle; A is selected from

each of Z, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—; Z⁵ and Z⁶ is independentlyselected from —C(H)— and —N—; B is selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle; C is selected from bond, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle; each of L¹, L², L³ and L⁴ isindependently selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, and —N(R⁵¹)S(O)N(R⁵¹)— or from alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene, andheteroalkynylene, each of which is optionally substituted with one ormore R⁵⁰, wherein two R⁵⁰ groups attached to the same atom or differentatoms of any one of L¹, L², or L³ can together optionally form a bridgeor ring; R⁵⁰ is, at each occurrence, independently selected from:halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(R⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²); C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —N53R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵⁰ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁵¹ is independently selected at each occurrence from:hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴; C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂carbocycle and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵¹ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁵² is independently selected at each occurrence fromhydrogen; and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, each of which is optionally substituted by halogen, —CN,—NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂carbocycle, or 3- to 6-membered heterocycle; R⁵³ and R⁵⁴ are takentogether with the nitrogen atom to which they are attached to form aheterocycle, optionally substituted with one or more R⁵⁰; R⁵⁷ isselected from: hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²52),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlysubstituted at each occurrence with one or more substituents selectedfrom —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,—NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,—OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR²C(O)R⁵²C(O)R, —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and R⁵⁸ is selected from hydrogen; andC₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; R^(A1) is, at each occurrence, independently selected fromhydrogen and R⁵⁰; R^(A2) is, at each occurrence, independently selectedfrom hydrogen and R⁵⁰; R^(B) is, at each occurrence, independentlyselected from R⁵⁰, or two R^(B) groups attached to the same atom ordifferent atoms can together optionally form a bridge or ring; R^(H2) isindependently selected at each occurrence from R⁵⁰, or two R^(H2) groupsattached to the same atom or different atoms can together optionallyform a bridge or ring; R^(C) is, at each occurrence, independentlyselected from hydrogen or R⁵⁰, or two R^(C) groups attached to the sameatom or different atoms can together optionally form a bridge or ring; ris an integer from 1 to 6; and each of m, p and q is independently aninteger from 0 to
 12. 3. The compound of claim 2, wherein the compoundof Formula (I-G) is represented by Formula (I-I):


4. The compound of claim 2 or 3, wherein L⁴ is selected from —O—, —S—,—NH— and —CH₂—.
 5. The compound of claim 4, wherein L⁴ is selected from—O— and —NH—.
 6. The compound of any one of claims 2-5, wherein R^(H2)is selected from halo, —C(O)R⁵², and —C(O)N(R⁵²)₂.
 7. The compound ofclaim 6, wherein R⁵² is selected from hydrogen and C₁₋₁₀ alkyl.
 8. Thecompound of any one of the preceding claims, wherein C is C₃₋₁₂carbocycle or 3- to 12-membered heterocycle.
 9. The compound of claim 8,wherein C is 5- to 12-membered heterocycle, wherein the heterocyclecomprises at least one nitrogen atom.
 10. The compound of claim 9,wherein C is aromatic.
 11. The compound of claim 9, wherein C issaturated.
 12. The compound of claim 11, wherein C is selected frompiperidinyl, piperazinyl, and morpholinyl.
 13. The compound of claim 12,wherein C is selected from:


14. The compound of claim 1 or 13, wherein R⁵⁷ is selected from—S(═O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵².
 15. Thecompound of any one of claims 1 or 14, wherein R⁵⁷ is selected from—S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(═O)₂NHCH₃. 16.The compound of any one of claims 1-15, wherein R^(C) is selected fromC₁₋₃ alkyl and C₁₋₃ haloalkyl.
 17. The compound of any one of claims1-12, wherein q is at least 1, and wherein R^(C) is selected fromhalogen, —N(R⁵²)₂, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂,C₁₋₃ alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached todifferent atoms can together form a C₁₋₃ bridge.
 18. The compound of anyone of claims 1 to 8, wherein: C is

W¹ is C₁₋₄ alkylene, optionally substituted with one or more R⁵⁰; W² isselected from a bond; and C₁₋₄ alkylene, optionally substituted with oneor more R⁵⁰; and W³ is selected from absent; and C₁₋₄ alkylene,optionally substituted with one or more R⁵⁰.
 19. The compound of claim18, wherein W¹, W² and W³ are each independently selected from C₁₋₄alkylene, wherein each C₁₋₄ alkylene is optionally substituted with oneor more R⁵⁰.
 20. The compound of claim 19, wherein W¹, W² and W³ areeach C₁ alkylene.
 21. The compound of claim 20, wherein W¹ and W² areeach C₁ alkylene and W³ is absent.
 22. The compound of any one of claims18-21, wherein R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. 23.The compound of any one of claims 1-22, wherein L³ comprises less than20 atoms.
 24. The compound of any one of claims 1-23, wherein L³ is nota bond.
 25. The compound of any one of claims 1-24, wherein L³ is C₁₋₆alkylene, optionally substituted with one or more R⁵⁰.
 26. The compoundof claim 24, wherein L³ is C₂ alkylene substituted with at least oneC₁₋₃ alkyl or C₁₋₃ haloalkyl, and optionally further substituted withone or more R⁵⁰.
 27. The compound of any one of claims 1-26, wherein L³is substituted with ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl).
 28. Thecompound of claim 27, wherein L³ is substituted with —CH₃.
 29. Thecompound of any one of claims 1 to 26, wherein L³ is selected from


30. The compound of claim 29, wherein R⁵⁰ is methyl.
 31. The compound ofany one of claims 1 to 25, wherein L³ is selected from

wherein any one of which is optionally substituted with one or more R⁵⁰.32. The compound of any one of claims 1 to 24, wherein L³ is selectedfrom

wherein any one of which is optionally substituted with one or more R⁵⁰.33. The compound of any one of claims 1 or 8-32, wherein: H is 5- to12-membered heterocycle; and B is 5- to 12-membered heterocycle or C₄₋₈carbocycle.
 34. The compound of any one of claims 1-33, wherein B is 6-to 12-membered bicyclic heterocycle.
 35. The compound of claim 34,wherein B comprises at least one nitrogen atom.
 36. The compound ofclaim 35, wherein B is

wherein each of E and G is independently N or C.
 37. The compound ofclaim 35, wherein B is indolylene.
 38. The compound of claim 37, whereinB is


39. The compound of any one of claims 1-33, wherein B is phenylene or


40. The compound of any one of claims 1-39, wherein R^(B) is selectedfrom halogen, methyl, —CN, —OR⁵², and —N(R⁵²)₂.
 41. The compound of anyone of claims 1 or 8-40, wherein H is 6-membered to 12-membered bicyclicheterocycle.
 42. The compound of any one of claims 1 or 8-41, wherein: His

each of X¹ and X² is independently selected from CR² and N; each of X³and X⁴ is independently selected from C and N; each of X⁵ and X⁶ isindependently selected from CR⁵³, N, —NR⁴, O, and S; each of R¹, R² andR³ is independently selected at each occurrence from hydrogen and R⁵⁰;and R⁴ is selected from R⁵¹.
 43. The compound of claim 42, wherein X³and X⁴ are each C.
 44. The compound of claim 42 or 43, wherein X⁶ isCR⁵³, and R³ is selected from hydrogen, halogen, —OR⁵², —N(R⁵²)₂, —CN,—C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl.
 45. The compound of claim 42,wherein H is


46. The compound of claim 45, wherein R² is selected from hydrogen,halogen, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl.
 47. Thecompound of claim 1, having the structure:

wherein each of R¹, R² and R³ is independently selected at eachoccurrence from hydrogen and R⁵⁰.
 48. The compound of claim 47, havingthe structure:


49. The compound of claim 48, wherein R² is selected from halogen,—OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl.
 50. Thecompound of any one of claims 45-49, wherein R³ is selected fromhydrogen, halogen, —OR⁵², —N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃haloalkyl.
 51. The compound of any one of claims 42-50 wherein R¹ isC₁₋₃ haloalkyl.
 52. The compound of claim 51, wherein R¹ is


53. The compound of any one of claims 1 or 8-41, wherein H isthienopyrimidinyl or thienopyridinyl.
 54. The compound of any one ofclaims 1 or 8-41, wherein: H is

each of X¹ and X² is independently CR² or N; each of X⁷, X⁸, X⁹, and X¹⁰is independently CR¹⁶, CR¹⁷R¹⁸, N, —NR¹⁹, O, or S; each of R¹⁶, R¹⁷, andR¹⁸ is independently selected at each occurrence from hydrogen and R⁵⁰;and R¹⁹ is selected from R⁵¹.
 55. The compound of any one of claims42-44 or 54, wherein X¹ is CR², and R² is selected from hydrogen,halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵²,C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. 56.The compound of any one of claims 42-44, 54, or 55, wherein X² is N. 57.The compound of any one of claims 1 or 8-40, wherein H is 5- or6-membered monocyclic heterocycle.
 58. The compound of claim 57,wherein: H is

each of Y¹, Y², and Y⁴ is independently CR², N, —NR²¹, O, or S; Y⁵ isCR²⁰, N, —NR²¹, O, or S; Y⁶ is C or N; Y³ is a bond, CR²², or N, whereinwhen Y³ is CR²² or N, then each of Y¹, Y², and Y⁴ is independently CR²,N, or NR²¹ and Y⁵ is CR²⁰, N, or NR²¹; each of R² and R²⁰ isindependently selected at each occurrence from hydrogen and R⁵⁰; and R²¹is selected from R⁵¹.
 59. The compound of any one of claims 1-58,wherein: A is


60. The compound of any one of claims 1-58, wherein: A is


61. The compound of claim 59 or 60, wherein Z⁵ and Z⁶ are N.
 62. Thecompound of any one of claims 59-61, wherein R^(A1) is, at eachoccurrence, independently selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkoxy, —CN, —NO₂, and —OH.
 63. Thecompound of any one of claims 59-62, wherein R^(A2) is, at eachoccurrence, independently selected from hydrogen, halo, C₁₋₄ alkyl, C₁₋₄alkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkoxy, —CN, —NO₂, and —OH.
 64. Thecompound of any one of claims 1-63, wherein L¹ is a bond or —N(R⁵¹)—.65. The compound of any one of claims 1-63, wherein L¹ is not a bond.66. The compound of any one of claims 1-63, wherein L¹ is —NH—.
 67. Thecompound of any one of claims 1-66, wherein L² is not a bond.
 68. Thecompound of any one of claims 1-67, wherein L² is alkylene orheteroalkylene, each of which is optionally substituted with one or moreR⁵⁰.
 69. The compound of any one of claims 1-68, wherein L² is C₁₋₄alkylene, optionally substituted with one or more R⁵⁰.
 70. The compoundof claim 69, wherein L² is substituted with ═O.
 71. The compound of anyone of claims 1-67, wherein L² is selected from —CH₂—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—.
 72. The compound of claim71, wherein L² is —CH₂—.
 73. The compound of claim 1, wherein: H is 5-to 12-membered heterocycle; B is indolylene; and C is 5- to 6-memberedheterocycle.
 74. The compound of claim 1, wherein: H isthienopyrimidinyl or thienopyridinyl; B is indolylene; and C ispiperidinyl, piperazinyl, or morpholinyl.
 75. The compound of claim 1,wherein: H is thienopyrimidinyl or thienopyridinyl; B is indolylene; andL¹, L², and L³ are not bonds.
 76. The compound of claim 1, wherein: H isthienopyrimidinyl; B is 6- to 12-membered bicyclic heterocycle; m is aninteger from 0 to 3; and p is an integer from 0 to
 3. 77. The compoundof claim 1, wherein: H is thienopyrimidinyl; B is indolylene; L¹ and L²are each independently selected from —O—, —S—, —NH—, and —CH₂—; L³ isselected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—,—OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene,alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, eachof which is optionally substituted with one or more R⁵⁰, wherein two R⁵⁰groups attached to the same atom or different atoms of L³ can togetheroptionally form a ring; R^(B) and R^(C) are each independently selectedat each occurrence from R⁵⁰, or two R^(B) groups or two R^(C) groupsattached to the same atom or different atoms can together optionallyform a ring; m is an integer from 0 to 3; p is an integer from 0 to 6;and q is an integer from 0 to
 6. 78. The compound of claim 1, wherein: His thienopyrimidinyl; B is indolylene; L¹ and L² are each independentlyselected from —O—, —S—, —NH—, and —CH₂—; L³ is selected from C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of which isoptionally substituted with one or more R⁵⁰; R^(B) and R^(C) are eachindependently selected at each occurrence from R⁵⁰, or two R^(B) groupsor two R^(C) groups attached to the same atom or different atoms cantogether optionally form a bridge or ring; m is an integer from 0 to 3;p is an integer from 0 to 3; and q is an integer from 0 to
 6. 79. Thecompound of any one of claims 76-78, wherein H is

and R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl,C₂₋₃ alkenyl, and C₂₋₃ alkynyl.
 80. The compound of claim 79, wherein R²is selected from —NH₂, —CH₃, and —NHCH₃.
 81. The compound of any one ofclaims 1-80, wherein A is selected from:


82. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: H is selectedfrom C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; A is selectedfrom

each of Z¹, Z², Z³, and Z⁴ is independently selected from—C(R^(A1))(R^(A2))—, —C(R^(A1))(R^(A2))—C(R^(A1))(R^(A2))—, —C(O)—, and—C(R^(A1))(R^(A2))—C(O)—, wherein no more than one of Z¹, Z², Z³, and Z⁴is —C(O)— or —C(R^(A1))(R^(A2))—C(O)—; Z⁵ and Z⁶ is independentlyselected from —C(H)— and —N—; B is selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle; C is selected from bond, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle; each of L¹, L², and L³ isindependently selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, and —N(R⁵¹)S(O)N(R⁵¹)— or from alkylene,alkenylene, alkynylene, heteroalkylene, heteroalkenylene, andheteroalkynylene, each of which is optionally substituted with one ormore R⁵⁰, wherein two R⁵⁰ groups attached to the same atom or differentatoms of any one of L¹, L², or L³ can together optionally form a bridgeor ring; R⁵⁰ is, at each occurrence, independently selected from:halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²); C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵⁰ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁵¹ is independently selected at each occurrence from:hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴; C₁₋₆ alkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂carbocycle and 3- to 12-membered heterocycle; and C₃₋₁₂ carbocycle and3- to 12-membered heterocycle, wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵¹ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(R⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl,and C₂₋₆ alkynyl; R⁵² is independently selected at each occurrence fromhydrogen; and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-memberedheterocycle, each of which is optionally substituted by halogen, —CN,—NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂carbocycle, or 3- to 6-membered heterocycle; R⁵³ and R⁵⁴ are takentogether with the nitrogen atom to which they are attached to form aheterocycle, optionally substituted with one or more R⁵⁰; R⁵⁷ isselected from: hydrogen, halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),—NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlysubstituted at each occurrence with one or more substituents selectedfrom —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,—NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,—OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,—P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),—P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and R⁵⁸ is selected from hydrogen; andC₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; R^(A1) is, at each occurrence, independently selected fromhydrogen and R⁵⁰; R^(A2) is, at each occurrence, independently selectedfrom hydrogen and R⁵⁰; each of R^(H) and R^(B) is, at each occurrence,independently selected from R⁵⁰, or two R^(H) groups or two R^(B) groupsattached to the same atom or different atoms can together optionallyform a bridge or ring; R^(C) is, at each occurrence, independentlyselected from hydrogen or R⁵⁰, or two R^(C) groups attached to the sameatom or different atoms can together optionally form a bridge or ring;and each of m, p, and q is independently an integer from 0 to
 12. 83.The compound of any one of claims 1-82, wherein the compound is providedas a substantially pure stereoisomer.
 84. The compound of claim 83,wherein the stereoisomer is provided in at least 90% enantiomericexcess.
 85. The compound of any one of claims 1-84, wherein the compoundis isotopically enriched.
 86. A pharmaceutical composition comprising acompound of any one of claims 1-85, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 87. Thepharmaceutical composition of claim 86, wherein the pharmaceuticalcomposition is formulated for oral administration.
 88. Thepharmaceutical composition of claim 86, wherein the pharmaceuticalcomposition is formulated for injection.
 89. A method of treating cancerin a subject in need thereof, comprising administering to the subject atherapeutically effective amount of a compound of any one of claims1-85, or a pharmaceutically acceptable salt thereof.
 90. A method oftreating a hematological cancer in a subject exhibiting a mutation inthe nucleophosmin (NPM1) gene, DNA (cytosine-5)-methyltransferase 3A(DNMT3A) gene, FMS-like tyrosine kinase-3 (FLT3) gene, isocitratedehydrogenase 1 (IDH1) gene, isocitrate dehydrogenase 2 (IDH2) gene, orcombination thereof, comprising administering to the subject atherapeutically effective amount of a compound of any one of claims1-85, or a pharmaceutically acceptable salt thereof.
 91. A method oftreating a hematological cancer in a subject in need thereof,comprising: a. determining the presence or absence of one or more of anNPM1 mutation, DNMT3A mutation, FLT3 mutation, IDH1 mutation, or IDH2mutation in a biological sample isolated from the subject; and b. if theone or more of the NPM1 mutation, DNMT3A mutation, FLT3 mutation, IDH1mutation, or IDH2 mutation is determined to be present in the subject,administering to the subject a therapeutically effective amount of acompound of any one of claims 1-85, or a pharmaceutically acceptablesalt thereof.
 92. The method of any one of claims 89-91, wherein thecancer is a hematological cancer.
 93. The method of claim 92, whereinthe cancer is leukemia.
 94. The method of claim 92, wherein the canceris lymphoma.
 95. The method of claim 92, wherein the cancer is mixedlineage leukemia (MLL), MLL-related leukemia, MLL-associated leukemia,MLL-positive leukemia, MLL-induced leukemia, rearranged mixed lineageleukemia (MLL-r), leukemia associated with a MLL rearrangement or arearrangement of the MLL gene, acute leukemia, chronic leukemia,indolent leukemia, lymphoblastic leukemia, lymphocytic leukemia, myeloidleukemia, myelogenous leukemia, childhood leukemia, acute lymphocyticleukemia (ALL), acute myeloid leukemia (AML), acute granulocyticleukemia, acute nonlymphocytic leukemia, chronic lymphocytic leukemia(CLL), chronic myelogenous leukemia (CML), myeloproliferative disease(MPD), myeloproliferative neoplasia (MPN), plasma cell neoplasm,multiple myeloma, myelodysplasia, cutaneous T-cell lymphoma, lymphoidneoplasm, AIDS-related lymphoma, thymoma, thymic carcinoma, mycosisfungoides, Alibert-Bazin syndrome, granuloma fungoides, Sezary Syndrome,hairy cell leukemia, T-cell prolymphocytic leukemia (T-PLL), largegranular lymphocytic leukemia, meningeal leukemia, leukemicleptomeningitis, leukemic meningitis, multiple myeloma, Hodgkin'slymphoma, non Hodgkin's lymphoma, or Waldenstrom's macroglobulinemia.96. The method of claim 92, wherein the cancer is selected from amalignant lymphoma, a leukemia, a mature B cell neoplasm, a mature Tcell and natural killer (NK) cell neoplasm, a precursor lymphoidneoplasm, Hodgkin lymphoma (HL), a plasma cell tumor, a mast cell tumor,a neoplasm of histiocytes and accessory lymphoid cells, animmunoproliferative disease, a myeloid leukemia, and a myelodysplasticsyndrome (MDS).
 97. The method of claim 92, wherein the cancer isselected from acute myeloid leukemia, acute lymphocytic leukemia,chronic myeloid leukemia, non-Hodgkin's lymphoma, multiple myeloma,mixed lineage leukemia and myelodysplastic syndromes.
 98. The method ofclaim 97, wherein the cancer is acute myeloid leukemia.
 99. A method oftreating a subject having acute myeloid leukemia or acute lymphoblasticleukemia, comprising: a. screening the subject for the presence of anMLL rearrangement, a partial tandem duplication of MLL, or elevatedMEIS1 expression levels; and b. administering a compound or salt of anyone of claims 1-85 to the subject if one or more of the MLLrearrangement, partial tandem duplication of MLL, or elevated MEIS1expression levels are determined to be present.
 100. A method oftreating insulin resistance, pre-diabetes, diabetes, or risk of diabetesin a subject in need thereof comprising administering to the subject atherapeutically effective amount of a compound of any one of claims1-85, or a pharmaceutically acceptable salt thereof.
 101. A method oftreating hyperglycemia in a subject in need thereof comprisingadministering to the subject a therapeutically effective amount of acompound of any one of claims 1-85, or a pharmaceutically acceptablesalt thereof.
 102. A method of treating a disease or conditionassociated with MLL fusion proteins, comprising administering to asubject in need thereof an effective amount of a compound of any one ofclaims 1-85.
 103. A method of treating a disorder mediated bychromosomal rearrangement on chromosome 11q23 in a subject in needthereof, the method comprising: administering to the subject atherapeutically effective amount of a compound of any one of claims1-85.
 104. A method of treating a disorder mediated by an interactionbetween menin and another protein, comprising administering to a subjectin need thereof a therapeutically effective amount of a compound of anyone of claims 1-85.
 105. The method of any one of claims 89-104, whereinthe subject is a human.
 106. A method of promoting proliferation of apancreatic cell, comprising administering a compound of any one ofclaims 1-85, or a pharmaceutically acceptable salt thereof.
 107. Themethod of claim 106, wherein the pancreatic cell is an islet cell. 108.The method of claim 106, wherein the pancreatic cell is a beta cell.109. The method of claim 108, wherein the beta cell proliferation isevidenced by an increase in beta cell production.
 110. The method ofclaim 108, wherein the beta cell proliferation is evidenced by anincrease in insulin production.
 111. The method of any one of claims106-110, further comprising administering the compound to a subject.112. The method of claim 111, wherein the subject suffers from diabetes.113. The method of claim 112, wherein the diabetes is type 1 diabetes.114. The method of claim 112, wherein the diabetes is type 2 diabetes.115. The method of claim 111, wherein the subject suffers fromprediabetes.
 116. The method of claim 111, wherein the subject suffersfrom impaired beta cell production.
 117. The method of claim 111,wherein the subject is human.
 118. A method of inhibiting an interactionof menin with one or more of MLL1, MLL2, a MLL fusion protein, and a MLLPartial Tandem Duplication, comprising contacting menin with aneffective amount of a compound of any one of claims 1-85.
 119. A methodof inhibiting a menin-MLL interaction, comprising contacting menin withan effective amount of a compound of any one of claims 1-85, whereininhibition of the interaction is evidenced by a reduction in expressionof a MLL fusion protein target gene.
 120. The method of claim 119,wherein the MLL fusion protein target gene is HOXA9, DLX2, PBX3, orMEIS1.
 121. A method of stabilizing menin, comprising contacting meninwith a compound of any one of claims 1-85.
 122. The method of any one ofclaims 118-121, wherein the contacting comprises contacting a cell thatexpresses menin.
 123. The method of any one of claims 118-121,comprising administering a second therapeutic agent.
 124. The method ofany one of claims 118-121, wherein the contacting takes place in vivo.125. The method of any one of claims 118-121, wherein the contactingtakes place in vitro.
 126. A kit comprising a pharmaceutical compositionof claim 86 and instructions for using the composition to treat asubject suffering from a disease or condition mediated by an interactionbetween menin and another protein.